Quinolinyl and benzothiazolyl modulators

ABSTRACT

Compounds, compositions and methods are provided that are useful in the treatment or prevention of a condition or disorder mediated by PPARγ. In particular, the compounds of the invention modulate the function of PPARγ. The subject methods are particularly useful in the treatment and/or prevention of diabetes, obesity, hypercholesterolemia, rheumatoid arthritis and atherosclerosis.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application No.10/278,851, filed Oct. 21, 2002, now abandoned which is a continuationof U.S. patent application No. 09/894,980, filed Jun. 27, 2001, now U.S.Pat. No. 6,583,157 which claims the benefit of U.S. provisionalapplication Ser. No. 60/214,810, filed Jun. 28, 2000. This applicationis related to U.S. patent application No. 60/073,042, filed Jan. 29,1998, and U.S. patent application No. 09/234,327, filed Jan. 20, 1999,now U.S. Pat. No. 6,200,995. This application is further related to U.S.patent application No. 60/141,672, filed Jun. 30, 1999, U.S. patentapplication No. 09/606,433, filed Jun. 28, 2000 and PCT Application No.U.S. 00/18 178, filed Jun. 28, 2000, now PCT Publication No. WO01/00579, the disclosures of each of the above being incorporated hereinby reference in their entirety.

The present invention relates to subject matter developed pursuant to aJoint Research Agreement between Tularik Inc. and Japan Tobacco, Inc.The Joint Research Agreement was executed by the parties on or aboutOct. 21, 1998.

The Joint Research Agreement related, in part, to development ofproducts that regulate leptin gene expression, including products thatmodulate the PPARYγ receptor. The present invention relates to comvoundsthat modulate the PPARγ receptor.

FIELD OF THE INVENTION

The present invention relates to compounds that modulate the PPARγreceptor and are useful in the diagnosis and treatment of type IIdiabetes (and complications thereof), hypercholesterolemia (and relateddisorders associated with abnormally high or low plasma lipoprotein ortriglyceride levels) and inflammatory disorders.

BACKGROUND OF THE INVENTION

The peroxisome proliferator-activated receptors (PPARs) are transducerproteins belonging to the steroid/thyroid/retinoid receptor superfamily.The PPARs were originally identified as orphan receptors, without knownligands, but were named for their ability to mediate the pleiotropiceffects of fatty acid peroxisome proliferators. These receptors functionas ligand-regulated transcription factors that control the expression oftarget genes by binding to their responsive DNA sequence as heterodimerswith RXR. The target genes encode enzymes involved in lipid metabolismand differentiation of adipocytes. Accordingly, the discovery oftranscription factors involved in controlling lipid metabolism hasprovided insight into regulation of energy homeostasis in vertebrates,and further provided targets for the development of therapeutic agentsfor disorders such as obesity, diabetes and dyslipidemia.

PPARγ is one member of the nuclear receptor superfamily ofligand-activated transcription factors and has been shown to beexpressed in an adipose tissue-specific manner. Its expression isinduced early during the course of differentiation of severalpreadipocyte cell lines. Additional research has now demonstrated thatPPARγ plays a pivotal role in the adipogenic signaling cascade. PPARγalso regulates the ob/leptin gene which is involved in regulating energyhomeostasis, and adipocyte differentiation which has been shown to be acritical step to be targeted for anti-obesity and diabetic conditions.

In an effort to understand the role of PPARγ in adipocytedifferentiation, several investigators have focused on theidentification of PPARγ activators. One class of compounds, thethiazolidinediones, which were known to have adipogenic effects onpreadipocyte and mesenchymal stem cells in vitro, and antidiabeticeffects in animal models of non-insulin-dependent diabetes mellitus(NIDDM) were also demonstrated to be PPARγ-selective ligands. Morerecently, compounds that selectively activate murine PPARγ were shown topossess in vivo antidiabetic activity in mice.

Despite the advances made with the thiazolidinedione class ofantidiabetes agents, unacceptable side effects have limited theirclinical use. Accordingly, there remains a need for potent, selectiveactivators of PPARγ which will be useful for the treatment of NIDDM andother disorders related to lipid metabolism and energy homeostasis.Still further, compounds that block PPARγ activity would be useful forinterfering with the maturation of preadipocytes into adipocytes andthus would be useful for the treatment of obesity and related disordersassociated with undesirable adipocyte maturation. Surprisingly, thepresent invention provides compounds that are useful as activators aswell as antagonists of PPARγ activity, compositions containing them andmethods for their use.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides methods of treating orpreventing a metabolic disorder or an inflammatory condition. Themethods typically involve administering to a subject in need thereof atherapeutically effective amount of a compound having the formula (I):

in which the symbol Ar¹ represents substituted or unsubstituted2-benzothiazolyl or substituted or unsubstituted quinolinyl; X is adivalent linkage selected from —O—, —C(O)—, —CH(R¹⁰)—, —N(R¹¹)—, and—S(O)_(k)—, wherein R¹⁰ is selected from hydrogen, cyano and(C₁-C₄)alkyl, R¹¹ is selected from hydrogen and (C₁-C₈)alkyl, and thesubscript k is an integer of from 0 to 2; with the proviso that when Ar¹is a substituted or unsubstituted 2-benzothiazolyl, then X is other than—S(O)_(k)—.

The letter Y represents a divalent linkage having the formula—N(R¹²)—S(O)₂—, wherein R¹² is hydrogen or (C₁-C₈)alkyl.

The symbol R¹ represents hydrogen, (C₂-C₈)heteroalkyl, halogen,(C₁-C₈)alkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷ or —N(R¹⁴)—C(O)—R¹⁷;wherein R¹⁴ is selected from hydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶ are independently selected fromhydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl, and aryl(C₁-C₄)alkyl,or taken together with the nitrogen to which each is attached form a 5-,6- or 7-membered ring; R¹⁷ is selected from (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; the subscript p is aninteger of from 0 to 3; and the subscript q is an integer of from 1 to2.

R² is substituted or unsubstituted aryl; and

R³ is selected from halogen and (C₁-C₈)alkoxy.

In another aspect, the present invention provides methods of treating orpreventing a condition or disorder mediated by PPARγ and methods formodulating PPARγ.

In yet another aspect, the present invention provides compounds offormula I and pharmaceutical compositions containing compounds offormula I.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The abbreviations used herein are conventional, unless otherwisedefined.

As used herein, “diabetes” refers to type I diabetes mellitus (juvenilediabetes) or type II diabetes mellitus (non-insulin-dependent diabetesmellitus or NIDDM), preferably, type II diabetes mellitus.

The terms “treat”, “treating” and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention” refer to a method ofdecreasing the probability or eliminating the possibility that a diseasewill be contracted.

As used herein, the term “PPARγ-mediated condition or disorder” and thelike refers to a condition or disorder characterized by inappropriate,e.g., less than or greater than normal, PPARγ activity. A PPARγ-mediatedcondition or disorder may be completely or partially mediated byinappropriate PPARγ activity. However, a PPAR γ -mediated condition ordisorder is one in which modulation of PPARγ results in some effect onthe underlying condition or disease (e.g., a PPARγ antagonist results insome improvement in patient well-being in at least some patients).Exemplary PPAR γ -mediated conditions and disorders include metabolicdisorders, e.g., diabetes, obesity, hyperglycemia, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia anddyslipidemia, and inflammatory conditions, e.g., rheumatoid arthritisand atherosclerosis.

The term “modulate” refers to the ability of a compound to increase ordecrease the function, or activity, of PPARγ. Modulation, as describedherein, includes the inhibition or activation of PPARγ, either directlyor indirectly. Inhibitors are compounds that, e.g., bind to, partiallyor totally block stimulation, decrease, prevent, delay activation,inactivate, desensitize, or down regulate signal transduction, e.g.,antagonists. Activators are compounds that, e.g., bind to, stimulate,increase, open, activate, facilitate, enhance activation, sensitize orup regulate signal transduction, e.g., agonists.

The term “therapeutically effective amount” refers to that amount of thecompound being administered sufficient to prevent development of oralleviate to some extent one or more of the symptoms of the condition ordisorder being treated.

The term “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicalsinclude groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. The term “alkyl,” unless otherwise noted, is also meant toinclude those derivatives of alkyl defined in more detail below as“heteroalkyl,” “cycloalkyl” and “alkylene.” The term “alkylene” byitself or as part of another substituent means a divalent radicalderived from an alkane, as exemplified by —CH₂CH₂CH₂CH₂—. Typically, analkyl group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, and wherein the nitrogenand sulfur atoms are optionally oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N and S may be placed atany interior position of the heteroalkyl group. The heteroatom Si may beplaced at any position of the heteroalkyl group, including the positionat which the alkyl group is attached to the remainder of the molecule.Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatomsmay be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Also included in the term “heteroalkyl” are thoseradicals described in more detail below as “heteroalkylene” and“heterocycloalkyl.” The term “heteroalkylene” by itself or as part ofanother substituent means a divalent radical derived from heteroalkyl,as exemplified by —CH₂—CH₂—S—CH₂CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Forheteroalkylene groups, heteroatoms can also occupy either or both of thechain termini. Still further, for alkylene and heteroalkylene linkinggroups, as well as all other linking group provided in the presentinvention, no orientation of the linking group is implied.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “fluoroalkyl,” aremeant to include monofluoroalkyl and polyfluoroalkyl.

The term “aryl,” employed alone or in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwise stated,an aromatic substituent which can be a single ring or multiple rings (upto three rings) which are fused together or linked covalently. The ringsmay each contain from zero to four heteroatoms selected from N, O, andS, wherein the nitrogen and sulfur atoms are optionally oxidized, andthe nitrogen atom(s) are optionally quaternized. The aryl groups thatcontain heteroatoms may be referred to as “heteroaryl” and can beattached to the remainder of the molecule through a heteroatom.Non-limiting examples of aryl groups include phenyl, 1-naphthyl,2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 2-benzothiazolyl, 5-benzothiazolyl, 2-benzoxazolyl,5-benzoxazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl,5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl, and6-quinolinyl. Substituents for each of the above noted aryl ring systemsare selected from the group of acceptable substituents described below.The term “arylalkyl” is meant to include those radicals in which an arylgroup is attached to an alkyl group (e.g., benzyl, phenethyl,pyridylmethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl” and “aryl”) aremeant to include both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″ R′″, —OC(O)R′, —C(O)R′,—CO₂R′, CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —CN and —NO₂ in a number ranging from zero to (2N+1), whereN is the total number of carbon atoms in such radical. R′, R″ and R′″each independently refer to hydrogen, unsubstituted (C₁-C₈)alkyl andheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C₁-C₄)alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.For example, —NR′R″ is meant to include 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like). Preferably, the alkylgroups (and related alkoxy, heteroalkyl, etc.) are unsubstituted or have1 to 3 substituents selected from halogen, —OR′, ═O, —NR′R″, —SR′,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —NR″C(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—CN and —NO₂. More preferably, the alkyl and related groups have 0, 1 or2 substituents selected from halogen, —OR′, ═O, —NR′R″, —SR′, —CO₂R′,—CONR′R″, —NR″C(O)R′, —CN and —NO₂.

Similarly, substituents for the aryl groups are varied and are selectedfrom halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂—, —CO₂R′,—CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, (C₁-C₈)alkyl and heteroalkyl,unsubstituted aryl, (unsubstituted aryl)-(C₁-C₄)alkyl, and(unsubstituted aryl)oxy-(C₁-C₄)alkyl. Preferably, the aryl groups areunsubstituted or have from 1 to 3 substituents selected from halogen,—OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂— —CO₂R′, —CONR′R″, —C(O)R′,—NR″C(O)R′, —S(O)₂R′, —S(O)₂NR′R″, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl. Still more preferably, the aryl groups have 0, 1or 2 substituents selected from halogen, —OR′, —NR′R″, —SR′, —R′, —CN,—NO₂— —CO₂R′, —CONR′R″, —NR″C(O)R′, —S(O)₂R′, —S(O)₂NR′R″,perfluoro(C₁-C₄)alkoxy, and perfluoro(C—C₄)alkyl.

Two of the substituents on adjacent atoms of the aryl ring mayoptionally be replaced with a substituent of the formula wherein T and Uare independently —NH—, —O—, —CH₂— or a single bond, and q is an integerof from 0 to 2. Alternatively, two of the substituents on adjacent atomsof the aryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—,—NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl ring may optionally bereplaced with a substituent of the formula —(CH₂), —X—(CH₂)_(t)—, wheres and t are independently integers of from 0 to 3, and X is —O—, —NR′—,—S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituent R′ in —NR′— and—S(O)₂NR′— is selected from hydrogen or unsubstituted (C₁-C₆)alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent drug. They may, for instance, be bioavailable by oraladministration whereas the parent drug is not. The prodrug may also haveimproved solubility in pharmacological compositions over the parentdrug. A wide variety of prodrug derivatives are known in the art, suchas those that rely on hydrolytic cleavage or oxidative activation of theprodrug. An example, without limitation, of a prodrug would be acompound of the present invention which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are all intended to beencompassed within the scope of the present invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

EMBODIMENTS OF THE INVENTION

A new class of compounds that modulate PPARγ has now been discovered.Depending on the biological environment (e.g., cell type, pathologicalcondition of the subject, etc.), these compounds of the presentinvention can activate or inhibit PPARγ activity. Thus, the compounds ofthe invention are useful in the treatment or prevention of conditionsand disorders associated with energy homeostasis, lipid metabolism,adipocyte differentiation and inflammation (see, Ricote et al. (1998)Nature 391:79-82 and Jiang et al. (1998) Nature 391:82-86). For example,compounds that activate PPARγ are useful in the treatment of metabolicdisorders, such as diabetes. Additionally, the compounds of theinvention are useful for the prevention and treatment of complicationsof metabolic disorders, such as diabetes, e.g., neuropathy, retinopathy,glomerulosclerosis and cardiovascular disorders.

In addition to their anti-diabetic activity, many synthetic PPARγligands also promote increased body weight gain, a situation that canaggravate the diabetic and obese condition. The ligands exemplifiedherein improve upon this profile by providing effective lowering ofserum glucose levels in the absence of such profound increases in bodyweight.

Related compounds of the more general class have in certain instancesbeen modified to produce pharmacologically active metabolites withexposures and in vivo lifetimes that exceed the parent compounds. In thetreatment of certain chronic conditions, such metabolites have beenlinked to untoward conditions. Some of the compounds contemplated by thepresent invention avoid the formation of such long-lived metaboliteswhile still maintaining the desirable pharmacological properties of thegeneral class.

PPARγ Modulators

The present invention provides compounds which are represented by theformula (I):

In formula I, the symbol Ar¹ represents a substituted or unsubstituted2-benzothiazolyl or substituted or unsubstituted quinolinyl group. Theletter X represents a divalent linkage selected from —O—, —C(O)—,—CH(R¹⁰)—, —N(R¹¹)—, and —S(O)_(k)—, wherein R¹⁰ is represents hydrogen,cyano or (C₁-C₄)alkyl; and R¹¹ represents hydrogen or (C₁-C₈) alkyl, andthe subscript k is an integer of from 0 to 2; with the proviso that whenAr¹ is a substituted or unsubstituted 2-benzothiazolyl, then X is otherthan —S(O)_(k)—.

The letter Y represents a divalent linkage having the formula—N(R¹²)—S(O)₂—, wherein R¹² is hydrogen or (C₁-C₈)alkyl. The symbol R¹represents hydrogen, (C₂-C₈)heteroalkyl, halogen, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴,—S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷ or —N(R¹⁴)—C(O)—R¹⁷, wherein R¹⁴ isselected from hydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl andaryl(C₁-C₄) alkyl; R¹⁵ and R¹⁶ are members independently selected fromhydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl, and aryl(C₁-C₄)alkyl,or taken together with the nitrogen to which each is attached form a 5-,6- or 7-membered ring; R¹⁷ is selected from (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; the subscript p is aninteger of from 0 to 3; and the subscript q is an integer of from 1 to2.

The symbol R² represents a substituted or unsubstituted aryl; and R³represents a halogen or (C₁-C₈)alkoxy.

One of skill in the art will understand that a number of structuralisomers are represented by formula I. In one group of embodiments, theisomers are those in which the groups on the phenyl ring occupypositions that are not contiguous. In other embodiments, the compoundsare those having the structural orientations represented by the formulae(Ia-Ij):

Ar¹ is Substituted or Unsubstituted 2-benzothiazolyl

A number of preferred embodiments are provided herein. For example, inone preferred embodiment, Ar¹ is a substituted or unsubstituted2-benzothiazolyl; X is —O— or —N(R¹¹)—; Y is —NH—S(O)₂—; R¹ is hydrogen,halogen, (C₁-C₈)alkoxy, (C₁-C₈)alkyl, —CO₂R¹⁴ or —C(O)NR¹⁵R¹⁶ whereinR¹⁴ is hydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl andaryl(C₁-C₄)alkyl, R¹⁵ and R¹⁶ are independently selected from hydrogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl, and aryl(C₁-C₄)alkyl, or takentogether with the nitrogen to which each is attached form a 5-, 6- or7-membered ring; R² is substituted or unsubstituted phenyl; and R³ ishalogen or (C₁-C₄)alkoxy.

In a further preferred embodiment, R¹ is selected from halogen, cyano,(C₁-C₈)alkoxy, (C₁-C₈)alkyl, —CO₂R¹⁴ and —C(O)NR¹⁵R¹⁶ wherein R¹⁴ is(C₁-C₈)alkyl; R¹⁵ and R¹⁶ are independently selected from hydrogen and(C₁-C₈)alkyl, or taken together with the nitrogen to which each isattached form a 5- or 6-membered ring.

In still other preferred embodiments, R¹ is selected from halogen,cyano, (C₁-C₈)alkoxy, and (C₁-C₈)alkyl. In yet other preferredembodiments, X is selected from —O— and —NH—. In still other preferredembodiments, R² is substituted phenyl having from 1 to 3 substituentsindependently selected from halogen, cyano, nitro, —OCF₃, —OH,—O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl.

In a particularly preferred embodiment of the invention, Ar¹ is asubstituted or unsubstituted 2-benzothiazolyl group; X is —O— or —NH—; Yis —NH—S(O)₂—;

-   R¹ is hydrogen, halogen, cyano, (C₁-C₈)alkoxy, (C₁-C₈)alkyl, —CO₂R¹⁴    or —C(O)NR¹⁵R¹⁶, wherein R¹⁴ is hydrogen or (C₁-C₈)alkyl; R¹⁵ and    R¹⁶ are independently selected from hydrogen and (C₁-C₈)alkyl, or    taken together with the nitrogen to which each is attached form a    5-, 6- or 7-membered ring; R² is substituted phenyl having from 1 to    3 substituents independently selected from halogen, cyano, nitro,    —OCF₃, —OH, —O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl; and R³ is halogen or    (C₁-C₄)alkoxy. Still further preferred are those embodiments in    which the compound is represented by a formula selected from:

In the most preferred embodiments, the compound is selected from:

Ar¹ is Substituted or Unsubstituted quinolinyl

In another group of preferred embodiments, Ar¹ is a substituted orunsubstituted quinolinyl group; X is selected from —O—, —S— and—N(R¹¹)—; Y is —N(R¹²)—S(O)₂—, wherein R¹² is selected from hydrogen and(C₁-C₈)alkyl; R¹ is selected from hydrogen, halogen, cyano,(C₁-C₈)alkoxy, (C₁-C₈)alkyl, —CO₂R¹⁴ and —C(O)NR¹⁵R¹⁶, wherein R¹⁴ isselected from hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl andaryl(C₁-C₄)alkyl, and R¹⁵ and R¹⁶ are independently selected fromhydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl, and aryl(C₁-C₄)alkyl,or taken together with the nitrogen to which each is attached form a 5-,6- or 7-membered ring; R² is substituted or unsubstituted phenyl; and R³is selected from halogen and (C₁-C₈)alkoxy.

Still further preferred are those compounds in which R¹ is selected fromhalogen, cyano, (C₁-C₈)alkoxy, (C₁-C₈)alkyl, —CO₂R¹⁴ and —C(O)NR¹⁵R¹⁶wherein R¹⁴ is (C₁-C₈)alkyl; R¹⁵ and R¹⁶ are independently selected fromhydrogen and (C₁-C₈)alkyl, or taken together with the nitrogen to whicheach is attached form a 5- or 6-membered ring.

In still other preferred embodiments, R¹ is selected from halogen,cyano, (C₁-C₈)alkoxy, and (C₁-C₈)alkyl. In yet other preferredembodiments, X is selected from —O—, —S— and —NH—. In still otherpreferred embodiments, Y is —NH—S(O)₂—. In other preferred embodiments,R² is substituted phenyl having from 1 to 3 substituents independentlyselected from halogen, cyano, nitro, —OCF₃, —OH, —O(C₁-C₆)alkyl, —CF₃,(C₁-C₈)alkyl.

In a particularly preferred embodiment of the invention, Ar¹ is asubstituted or unsubstituted quinolinyl group; X is —O—, —S— or —NH—; Yis —NH—S(O)₂—; R¹ is hydrogen, halogen, cyano, (C₁-C₈)alkoxy,(C₁-C₈)alkyl, —CO₂R¹⁴ or —C(O)NR¹⁵R⁶, wherein R¹⁴ is hydrogen or(C₁-C₈)alkyl; R¹⁵ and R¹⁶ are independently selected from hydrogen and(C₁-C₈)alkyl, or taken together with the nitrogen to which each isattached form a 5-, 6- or 7-membered ring; R² is substituted phenylhaving from 1 to 3 substituents independently selected from halogen,cyano, nitro, —OCF₃, —OH, —O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl; and R³ ishalogen or (C₁-C₄)alkoxy. Still further preferred are those embodimentsin which the compound is represented by a formula selected from:

In the most preferred embodiments, the compound is selected from:

In another aspect, the present invention provides pharmaceuticalcompositions comprising at least one of the above compounds in admixturewith a pharmaceutically acceptable excipient.

In yet another aspect, the present invention provides methods formodulating conditions mediated by PPARγ. More particularly, theconditions are selected from non-insulin-dependent diabetes mellitus,obesity, conditions associated with abnormal plasma levels oflipoproteins or triglycerides, and inflammatory conditions such as, forexample, rheumatoid arthritis and atherosclerosis.

Preparation of the Compounds

The compounds of the present invention can be prepared using standardsynthetic methods. Schemes 1-3 illustrate exemplary methods for thepreparation of compounds of structural formula (Ia). One of skill in theart will understand that similar methods can be used for the synthesisof compounds in the other structural classes.

As shown in Scheme I, compounds of the present invention can be preparedbeginning with commercially available 2-chloro-5-nitrobenzonitrile (i).Treatment of i with a phenol, thiophenol, or optionally protectedaniline in the presence of base and heat provides the adduct (ii).Reduction of the nitro group in ii with, for example, H₂ in the presenceof Raney nickel catalyst provides an aniline derivative (iii).Sulfonylation of iii with an appropriate arylsulfonyl halide (Ar¹SO₂C₁)in the presence of base (typically a tertiary amine) provides a targetcompound (iv). Compound iii can also be converted to a related compoundof formula (vi) in which the orientation of the sulfonamide linkage isreversed. Thus, conversion of the aniline iii to the benzenesulfonylchloride v can be accomplished using methods described in Hoffman,Organic Syntheses Collective Volume VII, pp. 508-511. Subsequenttreatment of v with an appropriate aniline provides the target compoundvi.

Scheme 2 depicts an alternative preparation of compounds of formula I(wherein Ar¹ is substituted or unsubstituted 2-benzothiazolyl and X is—O—).

Scheme 3 depicts an alternative preparation of compounds of formula I,wherein Ar¹ is substituted or unsubstituted 2-benzothiazolyl and X is—N(R¹¹)—.

Other compounds of the present invention can be prepared beginning with,for example, 3,4-difluoronitrobenzene, 3-chloro-4-fluoronitrobenzene,2-chloro-5-nitroanisole, 3-bromo-4-fluoronitrobenzene and the like.

Analysis of the Compounds

The compounds of the present invention can be evaluated for modulationof the PPARγ receptor using assays such as those described in Jiang, etal., Nature 391:82-86 (1998), Ricote, et al., Nature 391:79-82 (1998)and Lehmann, et al., J. Biol. Chem. 270(12): 12953-12956 (1995).Alternatively, the compounds can be evaluated for their ability todisplace radiolabeled BRL 49653 from a PPARγ-GST fusion protein asfollows:

Materials:

PPARγ-GST fusion protein (prepared according to standard procedures),[³H]-BRL 49653 having 50 Ci/mmol specific activity, PolyfiltronicsUnifilter 350 filtration plate and glutathione-Sepharose® beads (fromPharmacia: washed twice with 10× binding buffer in which BSA and DTI canbe left out).

Method:

Binding buffer (10 mM Tris-HCl, pH 8.0, 50 mM KCl, 10 mM DTT, 0.02% BSAand 0.01% NP-40) is added in 80-μL amounts to the wells of thefiltration plate. The test compound is then added in 10 μL of DMSO. ThePPARγ-GST fusion protein and radiolabeled BRL compound are premixed inbinding buffer containing 10 mM DTT and added in 10-μL amounts to thewells of the plate to provide final concentrations of 1 μg/well ofPPARγ-GST fusion protein and 10 nM [³H]-BRL 49653 compound. The plate isincubated for 15 min. Glutathione-agarose bead is added in 50 μL ofbinding buffer, and the plate is vigorously shaken for one hour. Theplate is washed four times with 200 μL/well of binding buffer (withoutBSA and DTT). The bottom of the plate is sealed and 200 μL/well ofscintillation cocktail is added. The top of the plate is then sealed andthe radioactivity is determined.

Compositions

The compounds of the present invention can administered via any suitableroute, most preferably orally or parenterally, in a preparationappropriately tailored to that route. Thus, the compounds of the presentinvention can be administered by injection, for example, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. The present invention also contemplates the use ofdepot formulations in which the active ingredient(s) is released over adefined time period. Also, the compounds described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present invention can be administered transdermally.Accordingly, the present invention also provides pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier orexcipient and either a compound of formula I or a pharmaceuticallyacceptable salt of a compound of formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from 5% or 10% to 70% of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use for the treatment of obesity, diabetes, inflammatoryconditions or other conditions or disorders mediated by PPARγ, thecompounds utilized in the pharmaceutical method of the invention areadministered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. A daily dose range of about 0.1 mg/kg to about 10 mg/kg ispreferred. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of thepractitioner. Generally, treatment is initiated with smaller dosageswhich are less than the optimum dose of the compound. Thereafter, thedosage is increased by small increments until the optimum effect underthe circumstances is reached. For convenience, the total daily dosagemay be divided and administered in portions during the day, if desired.

The compositions may be advantageously combined and/or used incombination with agents useful in the treatment and/or prevention ofmetabolic disorders and inflammatory conditions, complications thereofand pathologies associated therewith (e.g., cardiovascular disease andhypertension). In many instances, administration of the subjectcompounds or compositions in conjunction with these alternative agentsenhances the efficacy of such agents. Accordingly, in some instances,the present compounds, when combined or administered in combinationwith, e.g., anti-diabetic agents, can be used in dosages which are lessthan the expected amounts when used alone, or less than the calculatedamounts for combination therapy.

Suitable agents for combination therapy include those that are currentlycommercially available and those that are in development or will bedeveloped. Exemplary agents useful in the treatment of metabolicdisorders include, but are not limited to: (a) anti-diabetic agents suchas insulin, sulfonylureas (e.g., meglinatide, tolbutamide,chlorpropamide, acetohexamide, tolazamide, glyburide, glipizide andglimepiride), biguanides, e.g., metformin (Glucophage®), α-glucosidaseinhibitors (acarbose), thiazolidinone compounds, e.g., rosiglitazone(Avandia®), troglitazone (Rezulin®) and pioglitazone (Actos®); (b) β₃adrenergic receptor agonists, leptin or derivatives thereof andneuropeptide Y antagonists; (c) bile acid sequestrants (e.g.,cholestyramine and colestipol), HMG-CoA reductase inhibitors, e.g.,statins (e.g., lovastatin, atorvastatin, fluvastatin, pravastatin andsimvastatin), nicotinic acid (niacin), fibric acid derivatives (e.g.,gemfibrozil and clofibrate) and nitroglycerin. Exemplary agents usefulin the treatment of inflammatory conditions include, but are not limitedto: (a) non-steroidal antiinflammatory agents (NSAIDs) such as propionicacid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid,carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen,indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen,pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acidderivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin andzomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetyl salicylic acid and sulfasalazine) and thepyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone); (b) cyclooxygenase-2 (COX-2)inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®) and (c)inhibitors of phosphodiesterase type IV (PDE-IV).

Methods of Use

The present invention provides methods of using the foregoing compoundsand compositions to treat or prevent a metabolic disorder or aninflammatory condition. The present invention also provides methods ofusing the foregoing compounds and compositions to treat or prevent acondition or disorder mediated by PPARγ. The methods compriseadministering to a subject in need thereof a therapeutically effectiveamount of a compound of formula 1.

In still another aspect, the present invention provides methods of usingthe foregoing compounds and compositions to modulate PPARγ. The methodscomprise contacting a cell with the compound of formula I.

The following examples are offered by way of illustration and are notintended to limit the scope of the invention.

EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR spectra wererecorded on a Varian Gemini 400 MHz NMR spectrometer. Significant peaksare tabulated in the order: number of protons, multiplicity (s, singlet;d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet)and coupling constant(s) in Hertz (Hz). Electron Ionization (EI) massspectra were recorded on a Hewlett Packard 5989A mass spectrometer. Massspectrometry results are reported as the ratio of mass over charge,followed by the relative abundance of each ion (in parentheses). Intables, a single m/e value is reported for the M+H (or as noted M−H) ioncontaining the most common atomic isotopes. Isotope patterns correspondto the expected formula in all cases. Electrospray ionization (ESI) massspectrometry analysis was conducted on a Hewlett-Packard 1100 MSDelectrospray mass spectrometer using the HP1 100 HPLC for sampledelivery. Normally the analyte was dissolved in methanol at 0.1 mg/mLand 1 μL was infused with the delivery solvent into the massspectrometer which scanned from 100 to 1500 daltons (D). All compoundscould be analyzed in the positive ESI mode, using 1:1 acetonitrile/waterwith 1% acetic acid as the delivery solvent. The compounds providedbelow could also be analyzed in the negative ESI mode, using 2 mM NH₄OAcin acetonitrile/water as delivery solvent.

Abbreviations

Triethylamine (Et₃N), methanol (MeOH), dimethylsulfoxide (DMSO),N-methylmorpholine (NMM), dimethylformamide (DMF),4-(dimethylamino)pyridine (DMAP), 3-chloroperoxybenzoic acid (mCPBA),ethyl acetate (AcOEt), ethanol (EtOH), hexamethylphosphoramide (HMPA),acetic acid (AcOH), silver benzoate (AgOBz), tetrahydrofuran (THF),N-hydroxybenzotriazole (HOBT), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU),1-hydroxy-7-azabenzotriazole (HOAT),O—(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).

Certain intermediates used in preparing the compounds below aredescribed in co-pending U.S. patent application Ser. No. 09/606,433,filed Jun. 28, 2000.

Example 1

The following benzenesulfonyl chlorides were prepared by the procedureof R. V. Hoffman (Org. Syn. Coll. Vol. VII, 508-511) from thecorresponding commercially available anilines and used to make theindicated examples.

2-Chloro-4-t-butylbenzenesulfonyl chloride (1a)

Yield 34%. ¹H NMR (CDCl₃) δ 8.06 (1H, d, J=8.4 Hz), 7.62 (1H, s), 7.48(1H, d, J=8.4 Hz), 1.37 (9H, s); m.p. 68.8° C.

2-Trifluoromethyl-4-chlorobenzenesulfonyl chloride (1b) Yield 76% as asolid. ¹H NMR (CDCl₃) δ 8.325 (d, J=8.4 Hz, 1H), 7.966 (br s, 1H), 7.829(br d, J=8.4 Hz, 1H). m.p. 37.0° C. 2-Chloro-4-methylbenzenesulfonylchloride (1c)

Yield 47% as an oil.

¹H NMR (CDCl₃) δ 8.02 (1H, d, J=8.8 Hz), 7.46 (1H, s), 7.28 (1H, d,J=8.8 Hz), 2.47 (3H, s)

Example 2

Compound 2.3

Compound 2.1 was prepared by a modification of the published procedureof Albert and Barlin (J. Chem. Soc. 2384-2396 (1959)). 3-Aminoquinoline(15.0 g, 105 mmol) was suspended in a mixture of 10N HCl (40 mL), ice(21 g) and water (100 mL) at 0-5° C., before sodium nitrite (7.6 g, 110mmol) was added slowly. The mixture was then added portionwise toanother solution of potassium ethyl xanthate (20.8 g, 125 mmol) in water(60 mL) at 45° C. The mixture was heated for 1 h before cooling off. Themixture was then extracted with ether. The ethereal solution was washedwith 2N NaOH solution, water, and brine before drying over magnesiumsulfate. After filtration, the removal of the solvent gave a brown oil(15 g), which was then dissolved in ethanol (150 mL) and refluxed withKOH (25 g) under nitrogen overnight. The ethanol solvent was thenremoved under vacuum, and the residue was separated between water andether. The ethereal solution was discarded. The aqueous solution wasacidified to pH=˜4, before it was extracted with ether. Then etherealsolution was washed with brine, dried over magnesium sulfate, filteredand concentrated under vacuum to give crude product (7.5 g) as a brownoil. Subsequent flash chromatography with eluent (0%-5%-10% ethylacetate/dichloromethane) produced 3-mercaptoquinoline (2.1) (5.35 g, 32%yield) as a solid. ¹H NMR (DMSO) δ 9.02 (1H, d, J=2.3 Hz), 8.63 (1H, d,J=2.2 Hz), 7.95-8.05 (2H, m), 7.75-8.02 (1H, m), 7.60-7.67 (1H, m).

To a mixture of 3-mercaptoquinoline (2.1) (1.18 g, 7.33 mmol) and 1,2,3-chloro-5-nitrobenzene (1.66 g, 7.33 mmol) dissolved in ethanol (100mL), was added a THF solution of t-BuOK (7.5 mL, 1 M). The mixture wasthen heated at 80° C. overnight before cooling off. After the removal ofethanol solvent, the mixture was separated between ethyl acetate andwater. The organic solution was washed with brine, dried over magnesiumsulfate and filtered. The filtrate was then concentrated to give a crudeproduct, which was then flash chromatographed with eluent (10%hexanes/dichloromethane) to afford 2.2 (1.80 g, 70% yield) as a yellowoil. ¹H NMR (DMSO) δ 8.75 (1H, d, J=2.3), 8.51 (1H, s), 8.22 (1H, s),8.01 (1H, d, J=8.4 Hz), 7.92 (1H, d, J=7.6 Hz), 7.74-7.80 (1H, m),7.60-7.66 (1H, m).

An ethyl acetate solution (100 mL) of 2.2 (1.80 g, 5.1 mmol) and tinchloride (II) dihydrate (6.88 g, 30 mmol) was heated at reflux overnightbefore cooling off. The solution was then poured into 1N NaOH solution(400 mL). After stirring for 30 min, the mixture was separated, and theorganic solution was washed with water, saturated sodium bicarbonate andbrine. After drying over magnesium sulfate, the solution was filteredand concentrated under vacuum. The residue was mixed withdichloromethane (10 mL) and sonicated. Subsequent vacuum filtrationprovided the aniline 2.3 (1.35 g, 82% yield) as an off-white solid. ¹HNMR (DMSO) δ 8.61 (1H, d, J=2.4), 7.96 (1H, d, J=8.4 Hz), 7.88 (1H, d,J=8.2 Hz), 7.83 (1H, d, J=2.2 Hz), 7.67-7.72 (1H, m), 7.54-7.60 (1H, m).mp 213.2° C.

Example 3 Compound 3

The aniline 2.3 (250 mg, 0.78 mmol) and 2-chlorobenzenesufonyl chloride(339 mg, 1.60 mmol) were dissolved in a mixed solvent of THF (5 mL) anddichloromethane (5 mL). To the solution was added pyridine (0.185 mL,2.34 mmol) and catalytic amount of DMAP. The solution was heated at 50°C. to distill off dichloromethane, and then THF with assistance ofvacuum. The residue was flash chromatographed with eluent (2.5% ethylacetate/dichloromethane) to give sulfonamide 3 (see Table 1) (302 mg,78%) as an off-white solid. ¹H NMR (DMSO) δ 11.58 (1H, s), 8.61 (1H, d,J=2.4 Hz), 8.19 (1H, d, J=7.6 Hz), 7.83-8.00 (3H, m), 7.67-7.75 (3H, m),7.56-7.65 (2H, m), 7.31 (2H, s). MS (M+H) 494.9. mp: 219.6° C. Anal.calcd: C, 50.87; H, 2.64; N, 5.65; found C, 50.86; H, 2.62; N, 5.52.

TABLE 1

Compound k R_(a) R_(b) R_(c) R_(d) m/e (M + H) 3 0 Cl H H H 495 4.1 0 ClH Cl H 529 4.2 0 H H H H 461 4.3 0 Cl H CF₃ H 561 (M − H) 5.1 1 Cl H H H511 5.2 1 Cl H Cl H 543 (M − H) 5.3 1 H H H H 477

Example 4

The compounds of Table 1 were prepared by the method of Example 3 fromcompound 2.3 and the corresponding arylsulfonyl chloride.

Example 4.1

¹H NMR(DMSO) δ 11.66 (1H, broad), 8.63 (1H, d, J=2.3 Hz), 8.18 (1H, d,J=8.6 Hz), 7.85-8.00 (4H, m), 7.70-7.75 (2H, m), 7.57-7.62 (1H, m), 7.32(2H, s). MS (M+H) 529.0. mp 214.0° C. Elemental Analysis: theory C,47.56; H, 2.28; N, 5.28; Found C47.30, H 2.36, N 5.37.

Example 4.2

¹H NMR(DMSO): δ 11.22 (1H, s), 8.61 (1H, d, J=2.3 Hz), 7.82-7.98 (5H,m), 7.57-7.75 (5H, m), 7.34 (2H, s). MS (M+H) 461.0. mp 246.8° C.Elemental Analysis theory C, 54.67; H, 3.06; N, 6.07; found C, 54.71; H,3.05; N, 5.94.

Example 4.3

¹H NMR (DMSO) δ 11.70-12.00 (1H, broad), 8.60-8.67 (1H, m), 8.35-8.43(1H, m), 8.20-8.25 (1H, m), 7.56-8.06 (6H, m), 7.32-7.38 (2H, m). MS(M−H) 560.9. mp: 225.1° C. Elemental Analysis: theory C, 46.86; H, 2.15;N, 4.97; found C. 47.01, H 2.26, N 4.98.

Example 5 General procedure for sulfur oxidation to the sulfoxide

A naphthylthioether of Examples 3 or 4 (0.2 mmol) was dissolved in amixed solvent of dichloromethane (10 mL) and methanol (5 mL). To thesolution was added mCPBA (120 mg, 0.7 mmol, 77% pure) in six batchesover 20 min. intervals. Then the solution was washed with 5% sodiumthiosulfate solution, 1% sodium bicarbonate solution and brine and thendried over magnesium sulfate. After filtering, the filtrate wasconcentrated to give a crude product, which was then flashchromatographed with eluent (5%-30% ethyl acetate/dichloromethane) toafford the corresponding sulfoxide.

Example 5.1

¹H NMR (DMSO): δ 11.75 (1H, s), 8.82 (1H, s), 8.68 (1H, s), 8.15-8.20(2H, m), 8.09 (1H, d, J=8.5 Hz), 7.85-7.91 (1H, m), 7.67-7.75 (3H, m),7.57-7.64 (1H, m), 7.17 (2H, s). MS (M+H) 511. mp 239.5° C. withdecomposition. Elemental Analysis: theory C, 49.28; H, 2.56; N, 5.47;found C, 49.30; H, 2.63; N, 5.37.

Example 5.2

¹H NMR(DMSO): δ 11.5-12.0 (broad), 8.83 (1H, s), 8.68 (1H, s), 8.15-8.20(2H, m), 8.09 (1H, d, J=8.5 Hz), 7.85-7.92 (2H, m), 7.55-7.75 (2H, m),7.17 (2H, s). MS (M−H) 542.9. mp: 234.4. Elemental Analysis: theory C,46.17; H, 2.21; N, 5.13; found C, 45.97; H, 2.26; N, 4.92.

Example 5.3

¹H NMR(DMSO) δ 11.43 (1H, s), 8.81 (1H, s), 8.68 (1H, s), 8.18 (1H, d,J=8.2 Hz), 8.09 (1H, d, J=8.5 Hz), 7.82-7.90 (3H, m), 7.58-7.74 (4H, m),7.21 (2H, s). MS (M+H) 476.9. mp 261.8° C. with decomposition. ElementalAnalysis: theory C 52.83, H 2.96, N 5.87; found C, 52.71; H, 3.05; N,5.71.

Example 6 2-Amino-4-chloro-benzenethiol hydrochloride (6)

By the procedure of Danley et al. (1965) Can. J. Chem. 43:2610-2612,sodium tetrasulfide was obtained by dissolving sulfur (Aldrich, 9.6 g,300 mmol) in molten sodium sulfide nonahydrate (Aldrich, 24.0 g, 100mmol). This hot liquid was added to a solution of2,5-dichloronitrobenzene (Aldrich, 38.4 g, 200 mmol) in 95% ethanol (140mL). After the exothermic reaction had ceased, the mixture was refluxedfor 2 hours and filtered while hot. The precipitate was washed withwater (50 mL) and ethanol (50 mL) to give 37.7 g of intermediatetrisulfide as a yellow solid. ¹H NMR (CDCl₃) δ 8.83 (d, J=2.3 Hz, 1H),7.76 (d, J=8.6 Hz, 1H), 7.55 (dd, J=8.6, 2.3 Hz, 1H).

Concentrated hydrochloric acid (125 mL) was slowly (overnight, 15 hours)added to a well-stirred suspension of the trisulfide (37.7 g) describedabove and tin (Aldrich, 88 g, 737 mmol) in 95% ethanol (200 mL). Afterfiltration of the hot solution, the filtrate was allowed to stand atroom temperature overnight to precipitate the crude product. Theprecipitate was collected by filtration, washed with 1:1ethanol/concentrated HCl. Recrystalization from 1:1 MeOH/concentratedHCl gave compound 6 (13.8 g) as white needles. ¹H NMR (DMSO-d₆) δ 6.96(d, J=8.3 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.50 (dd, J=8.3, 2.3 Hz, 1H).

Example 7 2-Amino-4-methyl-benzenethiol hydrochloride (7)

bis-(4-Methyl-2-nitrophenyl)-trisulfide was prepared using the method inExample 6, starting from 4-chloro-3-nitro-toluene (Aldrich, 34.3 g, 200mmol), sulfur (Aldrich, 9.6 g, 300 mmol) and sodium sulfide nonahydrate(Aldrich, 24.0 g, 100 mmol) in 95% EtOH (150 mL). 27.7 g of thetrisulfide was obtained as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ8.21 (d, J=8.3 Hz, 1H), 8.07 (br s, 1H), 7.58 (dd, J=8.3, 1.3 Hz, 1H),2.48 (s, 3H).

Reduction of the bis-(4-Methyl-2-nitrophenyl)trisulfide as in Example 6gave compound 7 (11.3 g) as a mixture after recrystalization, but whichwas used directly in subsequent reactions.

Example 8 5-Chloro-2-(2,6-dichloro-4-nitro-benzyl)-benzothiazole (8)

By a modification of the procedure of D. L. Boger (J. Org. Chem.43:2296-2297 (1978)) a solution of P₂O₅/MeSO₃H (Aldrich, 7.5 g, 1:10,w:w) was treated with 2-amino-4-chlorobenzenethiol hydrochloride(Example 6, 1.96 g, 10.0 mmol) and (2,6-dichloro-4-nitrophenyl)-aceticacid (2.50 g, 10.0 mmol). The resulting mixture was stirred at roomtemperature for 1 hour, then heated at 90° C. overnight (15 hours).After cooled to room temperature, the reaction mixture was poured to iceand the resulting mixture was extracted 3× with EtOAc (50 mL). Theorganic layers were combined and washed twice with a brine solution (100mL), dried over Na₂SO₄, and concentrated under vacuum. The crude solidwas chromatographed (CH₂Cl₂) to yield 3.7 g (99%) of compound 8 as apale yellow solid. ¹H NMR (CDCl₃) δ 8.28 (s, 2H), 7.98 (d, J=1.9 Hz,1H), 7.76 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 4.87 (s, 2H).MS (M+H) 373.

The compounds of Table 2 were prepared using the method of Example 8.

TABLE 2

Compound A B 8 Cl Cl 9 Cl H 10 CF₃ Cl 11 CF₃ H 12 H Cl 13 H H 14 Me Cl15 Me H

Example 9 5-Chloro-2-(2-chloro-4-nitro-benzyl)-benzothiazole (9)

¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=2.3 Hz, 1H), 8.25 (dd, J=8.5, 2.4Hz, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.89 (d, J=8.5Hz, 1H), 7.48 (dd, J=8.6, 2.0 Hz, 1H), 4.77 (s, 2H). MS (M+H) 339.

Example 102-(2,6-Dichloro-4-nitro-benzyl)-5-trinfluoromethyl-benzothiazole (10)

¹H NMR (DMSO-d₆) δ 8.42 (s, 2H), 8.34 (d, J=8.4 Hz, 1H), 8.28 (br s,1H), 7.76 (d, J=8.4 Hz, 1H), 4.94 (s, 2H). MS (M+H) 407.

Example 11 2-(2-Chloro-4-nitro-benzyl)-5-trifluoromethyl-benzothiazole(11)

¹H NMR (CDCl₃) δ 8.33 (d, J=2.3 Hz, 1H), 8.27 (br s, 1H), 8.14 (dd,J=8.5, 2.3 Hz, 1H), 7.96 (br d, J=8.3 Hz, 1H), 7.63 (d, J=8.5 Hz, 2H)4.70 (s, 2H). MS (M+H) 371.

Example 12 2-(2,6-Dichloro-4-nitro-benzyl)-benzothiazole (12)

¹H NMR (DMSO-d₆) δ 8.41 (s, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.90 (d, J=7.9Hz, 1H), 7.50-7.38 (m, 2H), 4.94 (s, 2H). MS (M−H) 337.

Example 13 2-(2-Chloro-4-nitro-benzyl)-benzothiazole (13)

¹H NMR (CDCl₃) δ 8.35 (d, J=2.2 Hz, 1H), 8.25 (dd, J=8.4, 2.2 Hz, 1H),8.05 (d, J=7.9 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.3 (d, J=8.5 Hz, 1H),7.49 (t, J=7.9 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 4.76 (s, 2H). MS (M+H)305.

Example 14 2-(2,6-Dichloro-4-nitro-benzyl)-5-methyl-benzothiazole (14)

¹H NMR (DMSO-d₆) δ 8.41 (s, 2H), 7.91 (d, J=8.2 Hz, 1H), 7.71 (br s,1H), 7.25 (d, J=8.2 Hz, 1H), 4.85 (s, 2H), 2.41 (s, 3H). MS (M+H) 353.

Example 15 2-(2-Chloro-4-nitro-benzyl)-5-methyl-benzothiazole (15)

¹H NMR (DMSO-d₆) 8.35 (d, J=2.3 Hz, 1H), 8.24 (dd, J=8.5, 2.3 Hz, 1H),7.91 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.74 (br s, 1H), 7.25(dd, J=8.2, 1.0 Hz, 1H), 4.73 (s, 2H), 2.42 (s, 3H). MS (M−H) 317.

Examples 16-23

The compounds of Table 2 were reduced to the anilines of Table 3 usingone of the methods described below, as indicated in Table 3.

Method A

To a solution of the nitro compound in ethyl acetate (0.1 M) at refluxwas added tin (II) dichloride dihydrate (5 equiv.). After 0.5 to 2 h atreflux, the hot mixture is poured into a separatory funnel containing 2×the volume of ethyl acetate and 50 equiv. of 1N KOH, freshly preparedand still warm. The mixture is rapidly extracted and separated. Theorganic layer is washed with brine, dried over MgSO₄ and concentrated togive aniline which can usually be used directly in the next step.

Method B

See Example 39.

Method C

To a solution of nitro compound (7 mmol) in isopropanol (50 mL)/THF (20mL) was added a slurry (0.5 mL) of Raney Nickel in water. The reactionwas stirred under an atmosphere of hydrogen at ambient pressure andtemperature for 24 h. After filtration through a Celite plug, thesolution was concentrated under vacuum to afford the desired aniline.The residual Raney Nickel on the Celite plug was suspended inhalogenated solvent for deactivation.

TABLE 3

Compound A B Method 16 Cl Cl A 17 Cl H B 18 CF₃ Cl A 19 CF₃ H B 20 H ClB 21 H H B 22 Me Cl B 23 Me H B

Example 16 3,5-Dichloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenylamine(16)

¹H NMR (DMSO-d₆) δ 8.03 (d, J=8.4 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.45(dd, J=8.5, 2.2 Hz, 1H), 6.70 (s, 2H), 5.79 (s, 2H), 4.52 (s, 2H). MS(M+H) 343.

Example 17 3-Chloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenylamine(17)

¹H NMR (DMSO-d₆) δ 8.05-7.95 (m, 2H), 7.43 (dd, J=8.5, 2.1 Hz, 1H), 7.17(d, J=8.2 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.53 (dd, J=8.2, 2.2 Hz, 1H),5.44 (s, 2H), 4.36 (s, 2H). MS (M+H) 309.

Example 183,5-Dichloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenylamine(18)

¹H NMR (DMSO-d₆) δ 8.29 (br s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.72 (d,J=8.4 Hz, 1H), 6.70 (s, 2H), 5.81 (s, 2H), 4.56 (s, 2H). MS (M+H) 377.

Example 193-Chloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenylamine (19)

¹H NMR (DMSO-d₆) δ 8.25 (br s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.72 (dd,J=8.4, 1.3 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.54(dd, J=8.2, 2.2 Hz, 1H), 5.46 (s, 2H), 4.40 (s, 2H). MS (M+H) 343.

Example 20 4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenylamine (20)

¹H NMR (DMSO-d₆) δ 7.99 (dd, J=8.0, 0.6 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H),7.45 (td, J=8.2, 1.2 Hz, 1H), 7.38 (td, J=8.0, 1.0 Hz, 1H), 6.70 (s,2H), 5.78 (s, 2H), 4.51 (s, 2H). MS (M+H) 309.

Example 21 4-Benzothiazol-2-ylmethyl-3-chloro-phenylamine (21)

¹H NMR (DMSO-d₆) δ 7.98 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.47(td, J=7.9, 1.2 Hz, 1H), 7.38 (td, J=7.9, 1.0 Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.54 (dd, J=8.2, 2.2 Hz, 1H), 5.44 (s,2H), 4.35 (s, 2H). MS (M+H) 275.

Example 22 3,5-Dichloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenylamine(22)

¹H NMR (DMSO-d₆) δ 7.84 (d, J=8.2 Hz, 1H), 7.73 (br s, 1H), 7.21 (dd,J=8.2, 1.0 Hz, 1H), 6.69 (s, 2H), 5.77 (s, 2H), 4.48 (s, 2H), 2.43 (s,3H). MS (M+H) 323.

Example 23 3-Chloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenylamine(23)

¹H NMR (DMSO-d₆ ) δ 7.84 (d, J=8.2 Hz, 1H), 7.73 (s, 1H), 7.21 (d, J=8.2Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 6.65 (d, J=2.1 Hz, 1H), 6.52 (dd,J=8.2, 2.1 Hz, 1H), 5.41 (s, 2H), 4.32 (s, 2H), 2.43 (s, 3H). MS (M+H)289.

The compounds of Table 4 were prepared using conventional methods fromcompounds in Table 3 and corresponding arylsulfonyl chloride.

TABLE 4

Compound A B D E 24 Cl Cl CF₃ H 25 Cl Cl Cl H 26 Cl Cl Cl Me 27 Cl H CF₃H 28 CF₃ Cl CF₃ H 29 CF₃ Cl Cl H 30 CF₃ H CF₃ H 31 CF₃ H Cl H 32 H ClCF₃ H 33 H Cl Cl H 34 H Cl Cl Me 35 H H CF₃ H 36 Me Cl CF₃ H 37 Me H CF₃H

Example 242-Chloro-N-[3,5-dichloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]4-trifluoromethyl-benzenesulfonamide(24)

¹H NMR (DMSO-d₆) δ 11.56 (br s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.20 (d,J=1.1 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00-7.95 (m, 2H), 7.45 (dd,J=8.6, 2.1 Hz, 1H), 7.23 (s, 2H), 4.62 (s, 2H). MS (M−H) 583.

Example 252,4-Dichloro-N-[3,5-dichloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide(25)

¹H NMR (DMSO-d₆) δ 11.40 (br s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.05 (d,J=8.6 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 7.70 (dd,J=8.6, 2.1 Hz, 1H), 7.46 (dd, J=8.6, 2.0 Hz, 1H), 7.20 (s, 2H), 4.62 (s,2H). MS (M−H) 549.

Example 262,4-Dichloro-N-[3,5-dichloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]-5-methyl-benzenesulfonamide(26)

¹H NMR (DMSO-d₆) δ 11.33 (br s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 8.04(d, J=8.6 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.87 (s, 1H), 7.45 (dd,J=8.6, 1.9 Hz, 1H), 7.22 (s, 2H), 4.61 (s, 2H), 2.40 (s, 3H). MS (M−H)563.

Example 272-Chloro-N-[3-chloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(27)

¹H NMR (DMSO-d₆) δ 11.24 (br s, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.16 (br s,1H), 8.02 (d, J=8.6 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.96 (d, J=8.3 Hz,1H), 7.45 (d, J=8.3 Hz, 2H), 7.20 (d, J=2.0 Hz, 1H), 7.10 (dd, J=8.4,2.0 Hz, 1H), 4.47 (s, 2H). MS (M−H) 549.

Example 282-Chloro-N-[3,5-dichloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenyl]4-trifluoromethyl-benzenesulfonamide(28)

¹H NMR (DMSO-d₆) δ 11.56 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.27 (d, J=8.3Hz, 1H), 8.26 (br s, 1H), 8.20 (br s, 1H), 7.99 (dd, J=8.3, 1.0 Hz, 1H),7.73 (dd, J=8.2, 1.2 Hz, 1H), 7.24 (s, 2H), 4.67 (s, 2H). MS (M−H) 617.

Example 292,4-Dichloro-N-[3,5-dichloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide(29)

¹H NMR (DMSO-d₆) δ 11.41 (s, 1H), 8.29 (br s, 1H), 8.27 (d, J=8.6 Hz,1H), 8.15 (d, J=8.6 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.73 (dd, J=8.4,1.4 Hz, 1H), 7.70 (dd, J=8.6, 2.0 Hz, 1H), 7.21 (s, 2H), 4.67 (s, 2H).MS (M−H).

Example 302-Chloro-N-[3-chloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(30)

¹H NMR (DMSO-d₆) δ 11.25 (br s, 1H), 8.32-8.22 (m, 3H), 8.16 (br s, 1H),7.96 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H),7.21 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.52 (s, 2H). MS (M−H) 583.

Example 312,4-Dichloro-N-[3-chloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide(31)

¹H NMR (DMSO-d₆) δ 11.10 (br s, 1H), 8.28 (br s, 1H), 8.26 (d, J=8.5 Hz,1H), 8.08 (d, J=8.5 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.72 (dd, J=8.4,1.4 Hz, 1H), 7.65 (dd, J=8.6, 2.1 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.18(d, J=2.2 Hz, 1H), 7.10 (dd, J=8.3, 2.2 Hz, 1H), 4.52 (s, 2H). MS (M−H)549.

Example 32N-(4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenyl)-2-chloro-4-trifluoromethyl-benzenesulfonamide(32)

¹H NMR (DMSO-d₆) δ 11.54 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.20 (br s,1H), 7.99 (d, J=8.3 Hz, 2H), 7.88 (d, J=7.8 Hz, 1H), 7.46 (td, J=8.0,1.0 Hz, 1H), 7.40 (td, J=7.8, 0.9 Hz, 1H), 7.23 (s, 2H), 4.61 (s, 2H).MS (M−H) 549.

Example 33N-(4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenyl)-2,4-dichloro-benzenesulfonamide(33)

¹H NMR (DMSO-d₆) δ 11.38 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.00 (d, J=7.9Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.70 (dd,J=8.6, 2.0 Hz, 1H), 7.46 (m, 1H), 7.40 (m, 1H), 7.20 (s, 2H), 4.60 (s,2H). MS (M−H) 515.

Example 34N-(4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenyl)-2,4-dichloro-5-methyl-benzenesulfonamide(34)

¹H NMR (DMSO-d₆) δ 11.32 (s, 1H), 8.17 (s, 1H), 8.00 (d, J=7.9 Hz, 1H),7.90 (d, J=8.1 Hz, 1H), 7.88 (s, 1H), 7.46 (t, J=7.3 Hz, 1H), 7.39 (t,J=7.4 Hz, 1H), 7.16 (s, 2H), 4.60 (s, 2H), 2.40 (s, 3H). MS (M−H) 531.

Example 35N-(4-Benzothiazol-2-ylmethyl-3-chloro-phenyl)-2-chloro-4-trifluoromethyl-benzenesulfonamide(35)

¹H NMR (DMSO-d₆) δ 11.23 (br s, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.15 (br s,1H), 7.98 (d, J=7.9 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.1 Hz,1H), 7.46 (td, J=7.9, 1.0 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.38 (t,J=7.7 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.11 (dd, J=8.3, 2.1 Hz, 1H),4.46 (s, 2H). MS (M−H) 517.

Example 362-Chloro-N-[3,5-dichloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(36)

¹H NMR (DMSO-d₆) δ 11.54 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.19 (br s,1H), 8.00 (dd, J=8.2, 1.0 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.70 (br s,1H), 7.26-7.18 (m, 3H), 4.58 (s, 2H), 2.40 (s, 3H). MS (M−H) 563.

Example 372-Chloro-N-[3-chloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenyl]4-trifluoromethyl-benzenesulfonamide(37)

¹H NMR (DMSO-d₆) δ 11.22 (br s, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.15 (br s,1H), 7.45 (dd, J=8.3, 1.1 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.71 (br s,1H), 7.43 (d, J=8.4 Hz, 1H), 7.24-7.19 (m, 2H), 7.05 (dd, J=8.5, 2.2 Hz,1H), 4.43 (s, 2H), 2.41 (s, 3H). MS (M−H) 529.

Example 38

3-Hydroxyquinoline (prepared according to the procedure of Naumann, et.al., Synthesis, 1990, 4, 279-281)) (3 g) and1,2,3-trichloro-5-nitrobenzene (4.7 g) were dissolved in DMF (80 mL) andheated with cesium carbonate (7.4 g) for 2 h at 60° C. The reaction waspoured into ice/water (500 mL). The resulting off-white precipitate wascollected by filtration and rinsed with hexane to afford compound 38 asa solid (6.9 g) suitable for use in the next reaction. ¹H NMR in CDCl₃8.863 (d, J=2.2 Hz, 1H), 8.360 (s, 2H), 8.106 (d, J=8.6 Hz, 1H), 7.646(m, 2H), 7.529 (d, J=8.6 Hz, 1H), 7.160 (d, J=2.2 Hz, 1H).

Example 39

To a solution of compound 38 (6.9 g) in ethanol/THF/water (ratio40:20:10) was added ammonium chloride (3.3 g) and powdered iron (3.4 g).This mixture was heated to reflux for 5 h. The hot mixture was thenfiltered through Celite and concentrated. The residue was dissolved inethyl acetate and washed with saturated NaHCO₃ solution followed bywater and then brine. The solution was dried over magnesium sulfate andconcentrated to afford compound 39 as an off-white solid (5.6 g). ¹H NMRin (DMSO) δ 8.846 (d, J=2.9 Hz, 1H), 8.010 (m, 1H), 7.915 (m, 1H), 7.645(m, 1H), 7.560 (m, 1H), 7.401 (d, J=2.9 Hz, 1H), 6.778 (s, 2H), 5.762(s, 2H).

Treatment of the aniline 39 with various sulfonyl chlorides according toconventional methods gave the sulfonamides 40-44 of Table 5.

TABLE 5

Compound X Y V A B C D 40 H H Cl CF₃ H Cl H 41 H H Cl Cl H CF₃ H 42 H HCl Cl H Cl H 43 H H Cl Cl H Cl Me 44 H H H Cl H Cl H 45 CO₂Me H Cl Cl HCl H 46 H CO₂Me Cl Cl H Cl H 47 CO₂H H Cl Cl H Cl H 48 H CO₂H Cl Cl H ClH 49 Me H Cl Cl H Cl Me 50 H H F Cl H Cl Me

Example 40

¹H NMR (DMSO) δ 11.4-11.6 (1H, broad), 8.87 (1H, d, J=2.9 Hz), 8.15-8.22(2H, m), 8.00-8.08 (2H, m), 7.87 (1H, d, J=8.0 Hz), 7.55-7.68 (2H, m),7.47 (1H, d, J=2.9 Hz), 7.35 (2H, s). MS (M−H) 545. mp 98.8° C.

Example 41

¹H NMR (DMSO) δ 11.58 (1H, s), 8.86 (1H, d, J=2.9 Hz), 8.38 (1H, d,J=8.4 Hz), 8.23 (1H, s), 8.01 (1H, d, J=8.4 Hz), 7.86 (1H, d, J=8.1 Hz),7.53-7.68 (2H, m), 7.46 (1H, d, J=2.9 Hz), 7.34 (2H, s). MS (M−H) 545.0.

Example 42

¹H NMR (d₆-acetone) δ 9.9 (1H, br s), 8.794 (1H, d, J=2.9 Hz), 8.23 (1H,d, J=8.4 Hz), 8.035 (1H, br d, J=8.4 Hz), 7.793 (1H, d, J=1.5 Hz), 7.78(1H, m), 7.62-7.70 (2H, m), 7.57 (1H, td, J=6.8, 1.2 Hz), 7.476 (2H, s),7.364 (1H, d, J=2.6 Hz). MS (M−H) 511.0.

Example 43

¹H NMR (300 MHz/CDCl₃) δ 2.43 (3H, s), 7.10 (1H, d, J=3 Hz), 7.26 (2H,s), 7.48-7.64 (4H, m), 7.96 (1H, s), 8.09 (1H, d, J=8.7 Hz), 8.78 (1H,d, J=3 Hz). MS (M+H) 527. mp 233-235° C.

Example 44

¹H NMR (300 MHz/CDCl₃) δ 7.14 (1H, dd, J=2.6 Hz, J=8.9 Hz), 7.26 (1H, d,J=8.9 Hz), 7.33 (1H, d, J=2.6 Hz), 7.56-7.58 (2H, m), 7.66-7.69 (2H, m),7.87 (1H, m), 7.93 (1H, d, J=2.0 Hz), 8.00 (1H, m), 8.09 (1H, d, J=8.5Hz), 8.80 (1H, d, J=2.9 Hz), 11.06 (1H, brs). MS (M+H)) 479. mp 122° C.

Example 453-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-6-carboxylicacid methyl ester (45)

A solution of 3-(4-amino-2,6-dichlorophenoxy)-quinoline-6-carboxylicacid methyl ester (96) (0.93 mmol) and 2,4-dichlorobenzenesulfonylchloride (250 mg, 1.02 mmol) in pyridine (0.13 mL, 1.53 mmol) CH₂Cl₂(3.7 mL) was stirred at room temperature for 12 h. Sat NaHCO₃ was addedto the reaction mixture, which was then extracted twice with AcOEt.Organic layer was washed by brine, dried over anhydrous MgSO₄, andconcentrated. Crude residue was purified by column chromatography(hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 45 (237 mg,41%, in 3 steps). ¹H NMR (300 MHz, DMSO-d₆) δ 3.90 (3H, s), 7.31 (2H,s), 7.72 (1H, dd, J=1.8, 7.8 Hz), 7.79 (1H, d, J=3.0 Hz), 7.96 (1H, d,J=1.8 Hz), 8.11 (2H, s), 8.18 (1H, d, J=7.8 Hz), 8.64 (1H, s), 8.99 (1H,d, J=3.0 Hz), 11.42 (1H, br s). MS (M+H) 571.

Example 463-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-8-carboxylicacid methyl ester (46)

To a solution of 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-8-carboxylicacid methyl ester (99) (1.26 mmol) in pyridine (0.15 mL, 1.80 mmol) andCH₂Cl₂ (5 mL), was added 2,4-Dichlorolbenzenesulfonyl chloride (381 mg,1.55 mmol). The mixture was stirred at room temperature for 12 h. SatNaHCO₃ was added to the reaction mixture, which was then extracted twicewith AcOEt. Organic layer was washed by brine, dried over MgSO₄, andconcentrated. The crude residue was purified by column chromatography(hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 46 (506 mg,70%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 3.91 (3H, s), 7.31(2H, s), 7.57-7.65 (2H, m), 7.72 (1H, dd, J=2.1, 8.6 Hz), 7.83 (1H, d,J=8.6 Hz), 7.96 (2H, d, J=2.1 Hz), 8.03 (1H, d, J=8.6 Hz), 8.18 (1H, d,J=8.6 Hz), 8.94 (1H, d, J=2.1 Hz), 11.4 (1H, br s), MS (M+H) 571.

Example 473-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-6-carboxylicacid (47)

To a solution of3-[2,6-Dichloro-4-(2,4-dichlorobenzenesulfonylamino)-phenoxy]-quinoline-6-carboxylicacid methyl ester (45) (200 mg, 0.35 mmol) in THF/MeOH(2 mL/2 mL) wasadded 4N NaOH (0.1 mL, 0.4 mmol). This mixture was refluxed for 2.5 h.The reaction mixture was cooled to room temperature and was neutralizedwith 2N HCl, and then concentrated. The residue was extracted twice withAcOEt. Organic layer was washed by brine, dried over anhydrous MgSO₄,and concentrated to give a solid. Crude product was recrystallized byhexane/AcOEt to afford compound 47 (153 mg, 78%). ¹H NMR (300 MHz,DMSO-d₆) δ 7.16 (2H, s), 7.62 (1H, dd, J=2.0, 8.5 Hz), 7.73 (1H, d,J=2.9 Hz), 7.82 (1H, s), 8.08-8.11 (3H, m), 8.60 (1H, s), 8.95 (1H, d,J=2.9 Hz), 13.2 (1H, br s), MS (M+H) 557. mp 228-2.

Example 483-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-8-carboxylicacid (48)

To a solution of3-[2,6-Dichloro-4-(2-chloro-4-trifluoromethyl-benzenesulfonylamino)-phenoxy]-quinoline-8-carboxylicacid methyl ester (47) (402 mg, 0.7 mmol) in THF/MeOH=0.1 mL/0.3 mL wasadded 4N NaOH (0.2 mL, 0.77 mmol). The mixture was refluxed for 12 h.After cooling to room temperature the reaction mixture was filtered toremove insoluble materials. The filtrate was concentrated and theresidue was dissolved in aq NH4Cl and extracted twice with AcOEt.Organic layer was washed by brine, and dried over anhydrous MgSO₄, andconcentrated to afford compound 48 (197 mg, 50%) as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 7.32 (2H, s), 7.70-7.81 (2H, m), 7.90 (1H, d,J=2.2 Hz), 7.96 (1H, d, J=2.2 Hz), 8.17-8.19 (1H, m), 8.22-8.24 (1H, m),8.38-8.39 (1H, m), 9.11 (1H, d, J=2.2 Hz), 11.4 (1H, br s), 15.4 (1H, brs). MS (M+H) 557. mp 263-266° C.

Example 492,4-Dichloro-N-[3,5-dichloro-4-(6-methyl-quinoln-3-yloxy)-phenyl]-5-methyl-benzenesulfonamide(49)

To a solution of 3,5-Dichloro-4-(6-methyl-quinlin-3-yloxy)-phenylamine(100) (400 mg, 1.25 mmol) in pyridine (0.12 mL, 1.48 mmol)-CH₂Cl₂ (4 mL)was added 2,4-dichloro-5-methylbenzenesulfonyl chloride (325 mg, 1.25mmol). The mixture was stirred at room temperature for 12 h. Thereaction mixture was concentrated and the residue was purified by columnchromatography (hexane/AcOEt=2/1, 80 g of silica gel) to providecompound (49) (453 mg, 66%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆)δ 2.41 (3H, s), 2.44 (3H, s), 7.31 (3H, s), 7.49 (1H, d, J=8.7 Hz), 7.61(1H, s), 7.88-7.91 (2H, m), 8.19 (1H, s), 8.74 (1H, d, J=3.0 Hz), 11.3(1H, br s), MS (M+H) 541. mp 228-230° C.

Example 50

Part 1

3-Chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene (50.1)

To a solution of 3,4-difluoronitrobenzene 1.00 g in conc. H₂SO₄ (20 mL),was added portionwise Cl₂O in CCl₄ (25 mL, prepared as described by CadyG. H. et al. in Inorg. Synth. Vol 5, p. 156 (1957)). The mixture wasstirred at room temperature overnight. The mixture was poured intocrashed ice and extracted with Et₂O (30 mLx3). Combined ether layerswere washed with 10% Na₂SO₃ and brine, and dried over Na₂SO₄. Thesolvent was concentrated to about 10 mL (this solution contains3-chloro-4,5-difluoronitrobenzene). This solution was diluted withacetone (60 mL), and then 3-hydroxyquinoline 0.75 g and K₂CO₃ 2.2 g wereadded to this solution. The mixture was heated to reflux for 1.5 h.After cooling the reaction mixture was filtered through a short celitepad. The filtrate was concentrated to give an oil, which was thenpurified by column chromatography (silica gel, AcOEt:hexane=1:5) toprovide the intermediate compound 50.1 (0.980 g) as a yellow oil.

Part 2

3-Chloro-5-fluoro-4-(quinolin-3-yloxy)phenylamine (50.2)

To a solution of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene(50.1) (0.980 g) and NH4Cl (1.64 g) in EtOH (50 mL)-H₂O (5 mL), wasadded iron powder (1.92 g). The mixture was heated to reflux for 1 h.After cooling the reaction mixture was filtered through short celitepad. The filtrate was concentrated, diluted with sat.NaHCO₃ andextracted with AcOEt (30 mLx3). The combined organic layers were washedwith brine and dried over Na₂SO₄. Concentration of solvent afford crudeproduct, which was purified by column chromatography (silica gel,AcOEt:hexane=1:3) to provide aniline 50.2 (0.420 g) as a colorlesssolid.

Part 3

N-[3-Chloro-5-fluoro-4-(quinolin-3-yloxy)phenyl]-2,4-dichloro-5-methyl-benzenesulfonamide(50)

To a solution of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)phenylamine(50.2) (0.420 g) in pyridine (2.2 mL), was added2,4-dichloro-5-methylbenzenesulfonylchloride 0.360 g. The mixture wasstirred at room for 1 h. The reaction mixture was purified directly bycolumn chromatography (silica gel, AcOEt:hexane=1:3). The product wastriturated by hexane to give title compound (0.522 g). Yield 73% as asolid. 1H NMR (300 MHz/CDCl₃) δ 2.43 (3H, s), 7.05 (1H, d, J=2.6 Hz),7.09-7.11 (1H, m), 7.21 (1H, d, J=2.6 Hz), 7.36 (1H, brs), 7.49-7.66(4H, m), 7.96 (1H, s), 8.10 (1H, d, J=8.2 Hz), 8.80 (1H, brs). MS (M+H)511. mp 187° C.

Example 51 3-Chloro-4-(quinolin-3-yloxy)nitrobenzene (51)

To a solution of 3-hydroxyquinoline (1.00 g) and3-chloro-4-fluoronitrobenzene (1.21 g) in acetone (20 mL), was addedK₂CO₃ (2.86 g). The mixture was refluxed for 1 h. After cooling thereaction mixture was filtered through a short celite pad. The filtratewas concentrated to provide compound 51 (2.07 g, quant.) as a brown oil.¹H NMR (300 MHz/CDCl₃) δ 7.02 (1H, d, J=9.1 Hz), 7.61 (1H, m), 7.72-7.80(3H, m), 8.10-8.18 (2H, m), 8.45 (1H, d, J=2.7 Hz), 8.82 (1H, d, J=2.8Hz).

Example 52 3-Chloro-4-(quinolin-3-yloxy)phenylamine (52)

To a solution of nitrobenzene 51 (2.07 g) and NH₄Cl (1.84 g) in EtOH (40mL)-H₂O (10 mL), was added iron powder (1.92 g). The mixture was heatedto reflux for 1 h. After cooling the reaction mixture was filteredthrough short celite pad. The filtrate was concentrated, diluted withsat.NaHCO₃ (30 mL) and extracted with AcOEt (30 mL). The combinedorganic layers were washed with brine (30 mL) and dried over Na₂SO₄.Concentration of the solvent afforded the aniline 52 (1.77 g, 95%) as ayellow solid. ¹H NMR (300 MHz/CDCl₃) δ 3.77 (2H, brs), 6.63 (1H, dd,J=2.7 Hz, J=8.6 Hz), 6.83 (1H, d, J=2.7 Hz), 6.99 (1H, d, J=8.6 Hz),7.24 (1H, d, J=2.8 Hz), 7.49 (1H, m), 7.56-7.64 (2H, m), 8.08 (1H, m),8.86 (1H, J=2.8 Hz)

The structures for Examples 53-54 and 56-61 are illustrated in Table 6.

TABLE 6

Compound V W X Y Z MS (M − H) 53 Cl H Cl H H 372 54 H H H H H 304 56 HCl H H Me 352 57 Cl Cl H Cl H 406 58 Cl H H H Me 354 (M + H) 59 Cl H MeH H 354 (M + H) 60 Cl Cl H H H 372 61 Cl H SO₂Me H H 416

Example 53 Compound 53

2-amino-6-chlorobenzothiazole (3.68 g, 20 mmol) and1,2,3-trichloro-5-nitrobenzene (4.53 g, 20 mmol) were dissolved inanhydrous DMSO (10 mL). Solid K₂CO₃ (3.04 g, 22 mmol) was added and thereaction mixture heated to 150° C. for 4 h. Let cool, then poured into53 mL deionized water. A fine yellow solid precipitated which wascollected by filtration after attempts to dissolve the product in ethylacetate failed. The yellow solid was suspended in 100 mL of ethylacetate and heated to reflux. After cooling to room temperature,filtration, rinsing with ethyl acetate followed by hexanes, and dryingunder vacuum provided the nitro compound 53 as a yellow powder. (1.06 g)¹H NMR (d₆-DMSO) δ 8.37 (s, 2H); 7.76 (bs, 1H); 7.30 (dd, 1H); 7.23 (bs,1H). MS (M−H) 372.

Example 54 Compound 54

To a solution of 2-chloro-4-nitro aniline (2 g) and potassium t-butoxide(12 mmol) in THF (18 mL) was added a solution of 2-chlorobenzothiazole(2.75 g) in THF (6 mL). The mixture was heated at reflux overnight thenquenched into water (100 mL). The product is extracted with methylenechloride and purified by flash chromatography to afford compound 54 (300mg) as a yellow solid. ¹H NMR (d6-acetone) δ 9.74 (br s, 1H), 9.214 (brd, 1H), 8.346 (m, 2H), 7.891 (d, J=8 Hz, 1H), 7.794 (d, J=8 Hz, 1H),7.466 (t, J=7.2 Hz, 1H), 7.321 (t, J=7.2 Hz, 1H). MS (M−H) 304.

Example 55

Compound 55

By the method of Abuzar et al, (Ind. J. Chem 20B, 230-233 (1981))2-chloro-4-nitro phenylisothiocyanate (Lancaster) (0.95 g) was coupledwith 2-amino-4-chlorotoluene (0.69 g) in refluxing acetone to form themixed thiourea 55 (1.5 g). ¹H NMR (DMSO) δ 10.021 (s, 1H), 9.789 (s,1H), 8.373 (m, 1H), 8.197 (m, 2H), 7.441 (d, J=1.6 Hz, 1H), 7.315 (d,J=8.4 Hz, 1H), 7.268 (dd, J=8.4, 2. Hz, 1H), 2.237 (s, 3H). MS (M+H)356. CHN calc: 47.20% C, 3.11% H, 11.80% N. Found: 47.24% C, 3.15% N,11.69% N.

Example 56 Compound 56

To a cool solution of thiourea 55 (0.63 g) in chloroform (6 mL) wasadded bromine (0.6 g) slowly. The mixture was then heated to reflux for2 h. On cooling, the solids were collected by filtration and thentriturated with acetone to afford benzothiazole 56 as its HBR salt (0.5g). ¹H NMR (DMSO) δ 8.989 (br d, J=8.4 Hz, 1H), 8.365 (d, J=2.4 Hz, 1H),8.291 (dd, J=9.2, 2.8 Hz, 1H), 7.259 (m, 2H), 5.4 (br s), 2.557 (s, 3H).MS (M−H) 352. CHN calc for M+0.9HBr: 39.38% C, 2.34% H, 9.84% N; Found:39.44% C, 2.35% H, 9.66% N.

Example 57 Compound 57

By the method of Examples 55 and 56,2,6-dichloro-4-nitrophenylisothiocyanate was coupled with3,5-dichloroaniline to form the corresponding mixed thiourea which wascyclized with bromine to afford benzothiazole 57 suitable for use in thenext reaction. MS (M−H) 406

Example 58

By the method of Example 53, benzothiazole 58 was prepared in 78% yieldas a yellow solid. MS (M+H) 354.

Example 59

By the method of Example 53, benzothiazole 59 was prepared in 30% yieldas a yellow solid. MS (M+H) 354.

Example 60 Compound 60

2,7-dichlorobenzothiazole (0.85 g, 4.2 mmol) and2,6-dichloro-4-nitroaniline (2.1 g, 10.4 mmol) were dissolved inanhydrous DMSO (10 mL). Solid Cs₂CO₃ (4.1 g, 12.5 mmol) was added andthe reaction mixture heated to 80° C. for 16 h. Let cool, then pouredinto 200 mL DI water. Excess cesium carbonate was neutralized withacetic acid. The aqueous layer was extracted 2×100 mL of ethyl acetate.The combined organic layers were washed with saturated brine, dried overMgSO₄, filtered, and concentrated to a yellow-brown solid. Theinsolubility of this compound prevented purification, so the crudematerial was used directly in the next reaction. ¹H NMR (400 MHz)(d₆-acetone) δ 10.35 (bs, 1H); 8.36 (s, 2H); 7.37 (t, 1H); 7.30 (dd,1H); 7.21 (dd, 1H). MS (M−H) 371.9.

Example 61

By the method of Examples 55 and 56,2,6-dichloro-4-nitrophenylisothiocyanate (GB 1131780 (1966)) was coupledwith methyl-(4-aminophenyl )-sulfone to form the corresponding mixedthiourea which was cyclized with bromine to afford benzothiazole 61suitable for use in the next reaction. ¹H NMR (DMSO) δ 8.44 (s, 2H),8.28 (br s, 2H), 7.82 (br d, 1H), 7.41 (br d, 1H), 3.19 (s, 3H). MS(M−H) 416.

Examples 62-69

Reduction of the nitro derivatives of Table 6 by Method A described inExamples 16-23 gave the corresponding anilines illustrated in Table 7.

TABLE 7

Compound V X X Y Z MS (M + H) 62 Cl H Cl H H 344 63 H H H H H 276 64 HCl H H Me 324 65 Cl Cl H Cl H 378 66 Cl H H H Me 324 67 Cl H Me H H 32468 Cl Cl H H H 344 69 Cl H SO₂Me H H 388

Example 62

¹H NMR (d₆-acetone) δ 8.78 (s, 1H); 7.29 (d, 1H); 7.41 (d, 1H); 7.27 (d,1H); 6.86 (s, 2H); 5.42 (s. 1H). MS (M+H) 344.

Example 65

¹H NMR (DMSO) δ 10.09 (s, 1H), 7.48 (br s, 1H), 7.31 (d, J=1.8 Hz, 1H),6.72 (s, 2H), 5.91 (br s, 2H). MS (M+H) 378.

Example 68

Crude 58 was reduced with SnCl₂.2H₂O according to methods describedherein to afford compound 68 as a greenish/gray solid afterrecrystallization from hot ethyl acetate/hexanes (1.14 g). ¹H NMR(d₆-acetone) δ 8.87 (bs, 1H); 7.40 (dd, 1H); 7.30 (t, 1H); 7.11 (d, 1H);6.87 (s, 2H); 5.44 (bs, 2H). MS (M+H) 344.0.

Example 69

¹H NMR (DMSO) δ 10.08 (s, 1H), 8.31 (s, 1H), 7.76 (d, J=8.4 Hz, 1H),7.57 (d, J=8.4 Hz, 1H), 6.73 (s, 2H), 5.90 (s, 2H), 3.17 (s, 3H). MS(M−H) 388.

Examples 70-91

Sulfonation of the anilines of Table 7 by the method of Example 3 or oneof the methods below provides the compounds illustrated in Table 8.

Method D

To a solution of aniline in methylene chloride (10 mL/g) was addedsulfonyl chloride (1.1 to 1.5 equiv.) in methylene chloride. Thenpyridine (2 equiv.) is added. The mixture is slowly concentrated byplacing on a rotary evaporator at ambient pressure with bath temperatureat 40 to 60° C. After 2 to 18 h, the mixture is concentrated undervacuum and redissolved in methylene chloride. Flash chromatography with0-20% ethyl acetate in methylene chloride provides the desired productwhich can often be triturated with ether or hexane to provide solidproduct.

Method E

A solution of aniline (0.5 mmol) in acetone (3 mL) was treated with arylsulfonyl chloride (1 equiv.), 2,6-lutidine (1 equiv.) and catalytic DMAPovernight at ambient temperature. The reaction was diluted withmethylene chloride, washed with 1 N HCl and then brine. The organiclayer was concentrated then purified by flash chromatography to yield afoam which could often be crystalized by trituration with ether/hexane.

TABLE 8

Compound A B C D V W X Y Z MS (M − H) 70 Cl H Cl Me Cl H Cl H H 564 71Cl H Cl H Cl H Cl H H 550 72 Cl H CF₃ H Cl H Cl H H 584 73 Cl H Cl H H HH H H 482 74 Cl H CF₃ H H H H H H 516 75 Cl H Cl Me H H H H H 496 76 ClH Cl H Cl H Cl H Me 530 77 Cl H CF₃ H Cl H Cl H Me 564 78 Cl H Cl H ClCl H Cl H 584 79 Cl H CF₃ H Cl Cl H Cl H 618 80 Cl H Cl Me Cl Cl H Cl H598 81 Cl H Cl H Cl H H H Me 530 82 Cl H CF₃ H Cl H H H Me 564 83 Cl HCl Me Cl H H H Me 544 84 H H COMe H Cl H H H Me — 85 Cl H Cl H Cl H Me HH 530 86 Cl H CF₃ H Cl H Me H H 564 87 Cl H Cl Me Cl H Me H H 544 88 ClH Cl H Cl Cl H H H 550 89 Cl H CF₃ H Cl Cl H H H 584 90 Cl H Cl H Cl HSO₂Me H H 594 91 Cl H CF₃ H Cl H SO₂Me H H 628

Example 70

¹H NMR (d₆-acetone) δ 9.19 (bs, 1H); 8.51 (s, 1H); 7.74 (d, 1H); 7.72(s, 1H); 7.43 (s, 2H); 7.37 (d, 1H); 7.28 (dd, 1H); 2.46 (s, 3H). MS(M−H) 563.9

Example 71

¹H NMR (d₆-acetone) δ 9.19 (bs, 1H); 8.22 (d, 1H); 7.78 (d, 1H); 7.74(d, 1H); 7.67 (dd, 1H); 7.43 (s, 2H); 7.37 (d, 1H); 7.28 (dd, 1H). MS(M−H) 549.8.

Example 72

¹H NMR (d₆-acetone) δ 10.05 (bs, 1H); 9.22 (bs, 1H); 8.45 (d, 1H); 8.06(s, 1H); 7.98 (d, 1H); 7.73 (m, 1H); 7.45 (s, 2H); 7.36 (d, 1H); 7.28(dt, 1H). MS (M−H) 583.8.

Example 73

¹H NMR (d₆-acetone) δ 9.54 (bs, 1H); 8.56 (d, 1H); 8.12 (s, 1H); 7.78(m, 2H); 7.61 (m, 2H); 7.41 (d, 1H); 7.36 (t, 1H); 7.30 (dd, 1H); 7.20(s, 1H). MS (M−H) 482.0

Example 74

¹H NMR (d₆-acetone) δ 9.67 (br s, 1H); 9.07 (bs, 1H); 8.59 (d, 1H); 8.34(d, 1H); 8.04 (s, 1H); 7.91 (d, 1H); 7.77 (d, 1H); 7.61 (d, 1H); 7.42(d, 1H); 7.36 (t, 1H); 7.32 (dd, 1H); 7.20 (t, 1H). MS (M−H) 515.9

Example 75

¹H NMR (d₆-acetone) δ 9.47 (br s, 1H); 9.06 (br s, 1H); 8.55 (br s, 1H);8.05 (br s, 1H); 7.8-7.6 (m, 3H); 7.5-7.10 (m, 4H); 2.24 (s, 3H). MS(M+H) 497.9

Example 76

¹H NMR (DMSO) δ 10.96 (1H, s), 10.11 (1H, s), 8.12-8.22 (1H, broad),8.06 (1H, d, 8.6), 7.90 (1H, d, J=2.1 Hz), 7.65 (1H, dd, J=8.6, 2.1 Hz),7.23 (1H, d, J=3.5 Hz), 7.10-7.20 (3H, m), 2.44 (3H, s). MS (M−H) 529.8.

Example 77

¹H NMR (DMSO) δ 11.11 (1H, s), 10.11 (1H, s), 8.27 (1H, d, J=8.0 Hz),8.16 (2H, s), 7.94 (1H, d, J=8.6 Hz), 7.10-7.26 (4H, m), 2.43 (3H, s).MS (M−H) 563.9. mp 192.6° C.

Example 78

¹H NMR (DMSO) δ 11.49 (s, 1H), 10.44 (s, 1H), 8.164 (d, J=8.4 Hz, 1H)7.95 (d, J=2 Hz, 1H), 7.71 (dd, J=8.4, 2 Hz, 1H), 7.50 (br s, 1H), 7.35(d, J=1.6 Hz, 1H), 7.25 (s, 2H). MS (M−H) 584.

Example 79

¹H NMR (DMSO) δ 11.59 (s, 1H), 10.40 (s, 1H), 8.368 (d, J=8.4 Hz, 1H),8.20 (br s, 1H), 8.00 (br d, J=8.4 Hz, 1H), 7.48 (br s, 1H), 7.344 (t,J=1.6 Hz, 1H), 7.274 (d, J=1.6 Hz, 2H). MS (M−H) 618.

Example 80

¹H NMR (DMSO) δ 11.37 (s, 1H), 10.40 (s, 1H), 8.19 (br s, 1H), 7.90 (m,1H), 7.53 (br s, 1H), 7.35 (br s, 1H), 7.25 (br s, 2H), 2.415 (s, 3H).MS (M−H) 598.

Example 81

¹H NMR (d₆-DMSO) δ 11.44 (1H, broad s); 9.96 (1H, broad s); 8.33 (1H,d); 8.19 (1H, s); 7.99 (1H, dd); 7.43 (1H, broad s); 7.26 (2H, s); 7.07(1H, d); 6.97 (1H, t); 2.35 (3H, s). MS (M−H). 529.9

Example 82

¹H NMR (d₆-DMSO) δ 11.26 (1H, broad s); 9.96 (1H, broad s); 8.12 (1H,d); 7.93 (1H, d); 7.69 (1H, dd); 7.43 (1H, broad s); 7.23 (2H, s); 7.08(1H, d); 6.97 (1H, t); 2.36 (3H, s). MS (M−H) 564.

Example 83

¹H NMR (d₆-DMSO) δ 11.23 (1H, broad s); 9.96 (1H, broad s); 8.14 (1H,s); 7.88 (1H, s); 7.43 (1H, broad s); 7.24 (2H, s); 7.08 (1H, d); 6.97(1H, t); 2.40 (3H, s); 2.36 (3H, s). MS (M−H) 543.9.

Example 84

¹H NMR (d₆-DMSO) δ 11.02 (1H, broad s); 9.96 (1H, broad s); 8.16 (2H,d); 7.97 (2H, d); 7.43 (1H, broad s); 7.26 (1H, s); 7.07 (1H, d); 6.97(1H, t); 2.62 (3H, s); 2.36 (3H, s).

Example 85

¹H NMR (d₆-DMSO) δ 11.28 (1H, broad s); 9.79 (1H, broad s); 8.13 (1H,d); 7.93 (2H, d); 7.70 (1H, dd); 7.44 (1H, broad s); 7.21 (3H, s); 7.05(1H, d); 2.30 (3H, s). MS (M−H) 529.9.

Example 86

¹H NMR (d₆-DMSO) δ 11.43 (1H, broad s); 9.79 (1H, broad s); 8.34 (1H,d); 8.19 (1H, s); 7.99 (1H, d); 7.44 (1H, broad s); 7.24 (3H, s); 7.04(1H, d); 2.30 (3H, s). MS (M−H) 564.

Example 87

¹H NMR (d₆-DMSO) δ 11.22 (1H, broad s); 9.79 (1H, broad s); 8.15 (1H,s); 7.89 (1H, s); 7.44 (1H, broad s); 7.23 (3H, s); 7.04 (1H, d); 2.41(3H, s); 2.31 (3H, s). MS (M−H) 543.9.

Example 88

¹H NMR (d₆-acetone) δ 9.92 (bs, 1H); 9.35 (bs, 1H); 8.23 (d, 1H); 7.78(d, 1H); 7.67 (dd, 1H); 7.45 (s, 2H); 7.36-7.29 (m, 2H); 7.16 (dd, 1H).MS (M−H) 549.8.

Example 89

¹H NMR (d₆-acetone) δ 8.45 (d, 1H); 8.06 (s, 1H); 7.97 (d, 1H); 7.46 (s,2H); 7.33-7.29 (m, 2H); 7.16 (dd, 1H). MS (M−H) 583.8.

Example 90

¹H NMR (DMSO) δ 11.43 (br s, 1H), 10.40 (br s, 1H), 8.33 (br s, 1H),8.16 (d, J=8 Hz, 1H); 7.94 (d, J=2 Hz, 1H), 7.753 (dd, J=8.2, 2 Hz, 1H),7.71 (dd, J=8.4, 2 Hz, 1H), 7.55 (br s, 1H), 7.265 (s, 2H), 3.22 (s,3H). MS (M−H) 594.

Example 91

¹H NMR (DMSO) δ 11.55 (br s, 1H), 10.40 (br s, 1H), 8.38 (m, 2H), 8.22(br s, 1H), 8.02 (br d, 1H), 7.77 (dd, J=8.4, 2 Hz, 1H), 7.55 (br s,1H), 7.295 (s, 2H), 3.19 (s, 3H). MS (M−H) 628.

Example 92 3-Hydroxy-6-methylquinoline (92)

A solution of 3-Amino-6-methylquinoline [(1.21 g, 7.65 mmol), preparedaccording to J. Chem. Soc. 2024-2027 (1948) Morley et al.] in 6N H₂SO₄(25 mL) was cooled in an ice bath. To the solution NaNO₂ (560 mg, 8.10mmol) in water (2 mL) was added and stirred for 30 min at 0° C.Separately 5% H₂SO₄ was refluxed and above Diazo reaction mixture wasadded to this refluxing solution. After 30 min the reaction mixture wascooled to room temperature, and was neutralized by 6N NaOH. Theresulting insoluble material was collected by filtration. This solid wasrecrystallized by CHCl₃/AcOEt to afford compound (92) (348 mg, 29%). ¹HNMR (300 MHz, DMSO-d₆) δ 7.34 (1H, dd, J=1.9, 8.6 Hz), 7.42 (1H, d,J=2.8 Hz), 7.55 (1H, s), 7.79 (1H, d, J=8.6 Hz), 8.50 (1H, d, J=2.8 Hz).

Example 93 3-(2,6-Dichloro-4-nitro-phenoxy)-6-methyl-quinoline (93)

To a solution of 3-Hydroxy-6-methylquinoline (92) (348 mg, 2.19 mmol) inDMF (3.5 mL), was added NaH (60% oil suspension, 90 mg, 2.25 mmol) inone portion at room temperature. After 5 min 3,4,5-trichloronitrobenzene(509 mg, 2.25 mmol) in DMF (2 mL) was added and the reaction mixture washeated at 50° C. with stirring for 2 h. After cooling to roomtemperature. Ice/water was added to the reaction mixture, which was thenacidified with 2N HCl and extracted twice with AcOEt. Organic layer waswashed with brine, dried over anhydrous MgSO₄, and concentrated. Cruderesidue was purified by column chromatography (hexane/AcOEt4/1, 80 g ofsilica gel) to afford compound 93 (510 mg, 67%). ¹H NMR (300 MHz,DMSO-d₆) δ 7.52-7.57 (2H, m), 7.61 (1H, s), 7.94 (1H, d, J=8.6 Hz), 8.63(2H, s), 8.86 (1H, d, J=2.9 Hz).

Example 94 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid(94)

A solution of 3-(2,6-dichloro-4-nitro-phenoxy)-6-methyl-quinoline (93)(510 mg, 1.46 mmol) and chromium (VI) oxide (292 mg, 2.92 mmol) inCH₂SO₄/H₂O=2.4 mL/4.7 mL was heated at 100° C. while three 292 mgportions of chromic anhydride were added eight hour intervals. After 32h heating was stopped and allowed to stand overnight. Insoluble materialwas collected by filtration, and this solid was washed with water twiceto afford compound (94) (443 mg, 80%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.94(1H, d, J=3.0 Hz), 8.14 (2H, s), 8.56 (1H, s), 8.65 (2H, s), 9.09 (1H,d, J=3.0 Hz).

Example 95 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acidmethyl ester (95)

To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylicacid (94) (443 mg, 0.93 mmol) in dry THF (20 mL) was added CH₂N₂ in Et₂Osolution [Prepared from nitrosomethylurea (1.65 g) and 50% KOH (5 mL)].This mixture was stirred at room temperature for 1 h. AcOH (1 mL) wasadded to the reaction mixture, which was then concentrated. Sat NaHCO₃was added to the residue, which was extracted twice with AcOEt. Organiclayer was washed by brine, dried over anhydrous MgSO₄, and concentratedto afford compound 95 (415 mg). ¹H NMR (300 MHz, DMSO-d₆) δ 3.89 (3H,s), 5.75 (2H, br s), 6.76 (2H, s), 7.73 (1H, d, J=2.9 Hz), 8.09 (2H, s),8.67 (1H, s), 8.94 (1H, d, J=2.9 Hz).

Example 96 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-6-carboxylic acidmethyl ester (96)

To a solution of 3-(2,6-dichloro-4-nitro-phenoxy)-quinoline-6-carboxylicacid methyl ester (95) (0.93 mmol) and NH₄Cl (283 mg, 5.3 mmol) inEtOH/THF/water (8 mL/16 mL/1 mL) was added iron powder (296 mg, 5.3mmol). The reaction mixture was refluxed for 4 h. Insoluble materialswere removed by Celite pad, which was washed by THF, acetone and thenEtOH. The filtrate was concentrated, and sat NaHCO₃ was added andextracted twice with AcOEt. Organic layer was washed by brine, driedover anhydrous MgSO₄, and concentrated to afford compound 96 (372 mg,over weight). ¹H NMR (300 MHz, DMSO-d₆) δ 3.89 (3H, s), 5.75 (2H, s),6.76 (2H, s), 7.73 (1H, d, J=2.9 Hz), 8.09 (2H, s), 8.67 (1H, s), 8.94(1H, d, J=2.9 Hz).

Example 97 3-Hydroxy-8-quinolinecarboxylic acid methyl ester (97)

To the mixture of 8-quinoline carboxylic acid (500 mg, 2.89 mmol) in THF(80 mL) was added CH₂N₂ in Et₂O sol. [Prepared from nitrosomethylurea(1.65 g) and 50% KOH (5 mL)] at room temperature. The reaction mixturewas stirred for 12 h and then concentrated to give the intermediateester. ¹H NMR (300 MHz, DMSO-d₆) δ 3.92 (3H, s), 7.60-7.70 (2H, m),7.93-7.96 (1H, m), 8.14-8.17 (1H, m), 8.44-8.48 (1H, m), 8.97-8.99 (1H,m). To a solution of the intermediate 8-Quinolinecarboxylic acid methylester (2.89 mmol) in AcOH (4 mL) was added 30% H₂O₂ (0.6 mL). Thereaction mixture was heated at 85° C. for 7.5 h. The reaction mixturewas treated with sat NaHCO₃, and extracted six times with CHCl₃. Organiclayer was dried over anhydrous MgSO₄, and concentrated. Crude residuewas triturated with CHCl₃/toluene to provide compound 97 (256 mg, 44%,in 2 steps). ¹H NMR (300 MHz, DMSO-d₆) δ 3.89 (3H, s), 7.52 (1H, d,J=6.9 Hz), 7.57 (1H, d, J=1.5 Hz), 7.66 (1H, dd, J=1.5, 6.9 Hz), 7.95(1H, dd, J=1.5, 8.1 Hz), 8.63 (1H, d, J=2.7 Hz), 10.5 (1H, br s).

Example 98 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-8-carboxylic acidmethyl ester (98)

To a solution of 3-Hydroxy-8-quinolinecarboxylic acid methyl ester (97)(256 mg, 1.26 mmol) and 3,4,5-trichloronitrobenzene (294 mg, 1.30 mmol)in acetone (40 mL) was added K₂CO₃ (870 mg, 6.30 mmol). This mixture wasrefluxed for 3.5 h. The reaction mixture was cooled to room temperatureand insoluble materials were removed by Celite filtration. The filtratewas concentrated and the residue was purified by column chromatography.(hexane/AcOEt=4/1, 80 g of silica gel) to afford compound 98. ¹H NMR(300 MHz, DMSO-d₆) δ 3.92 (3H, s), 7.67 (1H, dd, J=7.3 Hz), 7.79 (1H, d,J=2.9 Hz), 7.88 (1H, dd, J=1.5, 7.3 Hz), 9.05 (1H, d, J=2.9 Hz).

Example 99 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-8-carboxylic acidmethyl ester (99)

To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-8-carboxylicacid methyl ester (98) (1.26 mmol) and NH4Cl (370 mg, 6.91 mmol) inEtOH/THF/H₂O=8 mL/4 mL/2 mL was added iron powder (386 mg, 6.91 mmol).The reaction mixture was refluxed for 3.5 h. After cooling to roomtemperature and insoluble materials were filtered by Celite filtration.The filtrate was concentrated and sat NaHCO₃ was added to the residue,which was extracted twice with AcOEt. Organic layer was washed by brine,dried over MgSO₄, and concentrated. Crude residue was purified by columnchromatography (hexane/AcOEt=2/1, 80 g of silica gel) to afford compound99 (543 mg). ¹H NMR (300 MHz, DMSO-d₆) δ 3.91 (3H, s), 5.77 (2H, br s),6.78 (2H, s), 7.50 (1H, d, J=3.0 Hz), 7.61 (1H, dd, J=8.1 Hz), 7.81 (1H,dd, J=1.4, 6.4 Hz), 8.08 (1H, dd, J=1.4 Hz, 6.4 Hz), 8.93 (1H, d, J=3.0Hz).

Example 100 3,5-Dichloro-4-(6-methyl-quinolin-3-yloxy)-phenylamine (100)

To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-6-methyl-quinoline(93) (1.30 g, 3.71 mmol) and NH4Cl (992 mg, 18.55 mmol) inEtOH/THF/H₂O=12 mL/2 mL/3 mL, was added iron powder (1.04 g, 18.55mmol). The mixture was refluxed for 4 h. Insoluble materials wereremoved by Celite filtration. The filtrate was concentrated and satNaHCO₃ was added to the residue, which was then extracted twice withAcOEt. Organic layer was washed with brine, dried over anhydrous MgSO₄,and concentrated to afford compound 100 (1.18 g, 98%). ¹H NMR (300 MHz,DMSO-d₆) δ 2.44 (3H, s), 5.75 (2H, br s), 6.77 (2H, s), 7.27 (1H, d,J=2.8 Hz), 7.48 (1H, d, J=8.6 Hz), 7.67 (1H, s), 7.89 (1H, d, J=8.6 Hz),8.74 (1H, d, J=2.8 Hz).

Example 101 2,6-Dichloro-benzothiazole (101)

2-Amino-6-chlorobenzothiazole (15.7 g, 85 mmol) in H₃PO₄ (85%) (470 mL)was heated to 100° C. and dissolved. Then clear solution was cooled andvigorously stirred by mechanical stirrer. NaNO₂ (17.6 g, 255 mmol) inwater (30 mL) was added slowly keeps the temperature below 0° C.Separately a solution of CuSO₄/5H₂O (85 g), NaCl (107 g) in water (350mL) was cooled to −5° C. and stirred by mechanical stirrer. Afterpotassium iodide starch paper's color was disappeared diazonium solutionwas keeping cold and added slowly to the copper chloride solution withvigorous stirring. The reaction mixture was allowed to warm to roomtemperature. After 1 h water (1 L) and ether (1 L) were added to thereaction mixture and extracted twice. Organic layer was washed by waterand dried over anhydrous MgSO₄ and concentrated. Crude residue waspurified by silica gel chromatography (H/A=4/1, 180 g of silica gel) toprovide title compound 101 (7.46 g, 48%).

Example 102 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine(102)

To the solution of 4-amino-2,6-dichloro phenol (6 g, 26.5 mmol) and2,6-dichlorobenzothiazole (101) (6 g, 29.4 mmol, 1.1 equiv.) in DMSO (25mL), was added K₂CO₃ (11 g, 80 mmol, 3.0 equiv.). The mixture wasstirred and heated to 160° C. After 5.5 h water (20 mL) was added to thereaction mixture, which was neutralized with 2N HCl., and was extractedwith AcOEt three times. And the organic layer was washed with brine andwas dried over anhydrous MgSO₄, and then concentrated. Crude residue waspurified by column chromatography (CHCl₃/acetone=9/1, 180 g of silicagel) to afford3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (102) as ablack solid (4.52 g, 49%). ¹H NMR (300 MHz, DMSO-d₆) δ 5.86 (2H, br s),6.74 (2H, s), 7.48 (1H, dd, J=2.1, 5.7 Hz), 7.70 (1H, d, 8.7 Hz), 8.10(1H, d, 2.1 Hz).

Example 1032-Chloro-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(103)

A solution of 3,5-dichloro-4-(6-chlorobenzothiazol-2-yloxy)-phenylamine(102) (2.0 g, 5.79 mmol) and3-chloro-4-trifluoromethylbenzenesulfonylchloride (1.7 g, 6.08 mmol) inpyridine (10 mL) was stirred at room temperature. After 3 h water wasadded to the reaction mixture, which was then acidify by 2N HCl.Reaction mixture was extracted twice with AcOEt. Organic layer waswashed by brine, dried over MgSO₄ and concentrated. Crude residue waspurified by column chromatography (H/A=4/1, 80 g of silica gel) toafford title compound 103 (2.11 g, 65%) as a white solid. mp 82-84′ ¹HNMR (400 MHz, DMSO-d₆) δ 7.32 (2H, s), 7.46 (1H, dd, J=2.2, 8.7 Hz),7.67 (1H, d, J=8.7 Hz), 8.00 (1H, d, 8.0 Hz), 8.14 (1H, d, J=2.2 Hz),8.20 (1H, s), 8.38 (1H, d, J=8.3 Hz), 11.6 (1H, br s). MS (M+H) 586

Example 1042,4-Dichloro-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]benzenesulfonamide(104)

A solution of 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine(102) (2.0 g, 5.79 mmol) and 2,4-dichloro benzenesulfonylchloride (1.5g, 6.08 mmol) in pyridine (10 mL) was stirred at room temperature for 12h. Water was added to the reaction mixture, which was then acidified by2N HCl. Reaction mixture was extracted twice with AcOEt. Organic layerwas washed by brine, dried over MgSO₄ and concentrated. Crude residuewas purified by column chromatography (H/A=4/1, 80 g of silica gel) toafford title compound (104) (1.49 g, 46%) as a white solid. Mp 73-75° C.¹H NMR (300 MHz, DMSO-d₆) δ 7.29 (2H, s), 7.46 (1H, dd, J=2.2, 8.8 Hz),7.69 (1H, d, J=8.8 Hz), 7.71 (1H, dd, J=2.2, 8.4 Hz), 7.95 (1H, d, J=2.2Hz), 8.14 (1H, d, J=2.2 Hz), 8.18 (1H, d, J=8.4 Hz), 11.5 (1H, br s). MS(M+H) 553.

Example 105 3,5-Dichloro-4-(6-methoxybenzothiazol-2-yloxy)phenylamine(105)

To a solution of 2-chloro-6-methoxy-benzothiazole (prepared as describedby Weinstock et. al., J.Med.Chem.30: p1166 (1987)) and4-Amino-2,6-dichlorophenol 1.3 g (available from Tokyo Chemical IndustryCo., Ltd.) in DMSO (9 mL), was added K₂CO₃ 3.12 g. The mixture washeated at 150° C. for 3 h. The reaction mixture was purified by columnchromatography (silica gel, AcOEt:hexane=1:2) to provide the aniline 105(1.43 g, 56%). mp 158-160° C. ¹H NMR (300 MHz/CDCl₃) δ 3.84 (3H, s),3.85 (2H, brs), 6.69 (2H, s) 6.97 (1H, dd, J=2.6 Hz, J=8.9 Hz), 7.18(1H, d, J=2.6 Hz), 7.61 (1H, d, J=8.9 Hz).

Example 1062-Chloro-N-[3,5-dichloro-4-(6-methoxybenzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(106)

To a solution of3,5-dichloro-4-(6-methoxybenzothiazol-2-yloxy)phenylamine (105) (1.40 g)in pyridine (5 mL), was added 2-chloro-4-trifluorobenzenesulfonamide1.15 g. The mixture was stirred at room temperature for 2 h. Thereaction mixture was purified directly by column chromatography (silicagel, AcOEt:hexane=1:3). The product was triturated by hexane to give thetitle compound 106 (1.97 g, 82%) as a colorless powder. mp 164-165° C.NMR (300 MHz/DMSO-d6) δ 3.79 (3H, s), 7.00 (1H, dd, J=2.9 Hz, J=8.8 Hz),7.31 (2H, s), 7.55 (1H, d, J=8.8 Hz), 7.58 (1H, d, J=2.9 Hz), 8.00 (1H,dd, J=1.5 Hz, J=8.1 Hz), 8.20 (1H, d, J=1.5 Hz), 8.37 (1H, d, J=8.1 Hz),11.59 (1H, brs). MS (M+H) 583.

Example 200

6-Chloro-benzothiazol-2-ylamine (200)

Concentrated sulfuric acid (VWR, 5.4 mL, 100 mmol) was added over a10-min period to a stirred solution of 4-chloroaniline (Aldrich, 25.52g, 200 mmol) in 130 mL of chlorobenzene. A thick suspension was formed.To the above suspension was added KSCN (Aldrich, 25.3 g, 260 mmol) andthe mixture was then heated to 110° C. for 6 h. The mixture was cooledto room temperature, diluted with 300 mL of hexanes and filtered. Theprecipitate was taken up in 500 mL of water, heated to 80° C. for 30min. Filtration gave 32.0 g product.

To a stirred solution of the above product in 120 mL of CHCl₃ at 10° C.was added bromine (Aldrich, 68.8 g, 430 mmol) over a 20 min period. Themixture was stirred at ambient temperature for 30 min and was thenrefluxed for 30 min. Filtration followed by washing the solid with CHCl₃and ether gave a yellow solid, which was suspended in acetone. Thisdischarged the yellow color, and filtration followed by washing withacetone and with ether gave a white solid. The solid was dissolved in800 mL of hot water and the cooled solution was brought to pH 9 withconcentrated NH₄OH. Filtration followed by washing with water gave 17.8g product. ¹H NMR (400 MHz, DMSO-d₆) δ 7.76 (d, J=2.0 Hz, 1H), 7.59 (s,2H), 7.29 (d, J=8.5 Hz, 1H), 7.21 (dd, J=8.5, 2.2 Hz, 1H). MS (EI): m/z185 (M+H).

Example 201

2-Amino-5-chloro-benzenethiol (201)

A solution of 6-chlorobenzothiazol-2-ylamine (Example 200, 17.8 g, 96.7mmol) and KOH (EM, 87 g, 1.55 mol) in 150 mL of water was refluxed for 2d. The mixture was cooled to room temperature and was diluted with ice.The solution was brought to pH 5 with concentrated HCl. The mixture wasextracted 3× with EtOAc (300 mL). The organic layers were combined andwashed twice with a brine solution (300 mL), dried over Na₂SO₄. Removalof the solvent under reduced pressure gave 10.5 g product. ¹H NMR (400MHz, DMSO) δ 7.20 (d, J=2.5 Hz, 1H), 6.93 (dd, J=8.6, 2.5 Hz, 1H), 6.69(d, J=8.6 Hz, 1H) 5.30 (s, 3H). MS (EI): m/z 160 (M+H).

Example 202

2-Chloro-6-nitro-benzenethiol (202)

To a solution of 2,3-dichloronitrobenzene (Aldrich, 19.2 g, 100 mmol) in300 mL of DMSO was added powdered Na₂S.9H₂O (Aldrich, 24.0 g, 100 mmol).The mixture was stirred at ambient temperature for 24 h, then wasdiluted with 2 L of water. The mixture was clarified by filtration andthe filtrate was acidified to pH 4 with con. HCl. The mixture wasextracted 3× with Et₂O (400 mL). The organic layers were combined andwashed twice with a brine solution (400 mL), dried over Na₂SO₄. Removalof the solvent under reduced pressure gave 18.4 g product. ¹H NMR (400MHz, DMSO) δ 8.11 (dd, J=8.3, 1.3 Hz, 1H), 7.93 (dd, J=8.0, 1.3 Hz, 1H),7.40 (td, J=8.2, 1.3 Hz, 1H) 5.06 (s, 1H). MS (EI): m/z 188 (M−H).

Example 203

Benzyl 2-chloro-6-nitrobenzenethiol ether (203)

To a solution of 2-chloro-6-nitro-benzenethiol (Example 202, 9.5 g, 50mmol) in 200 mL of DMF was added NaH (Aldrich, 2.60 g, 60%, 65 mmol).The mixture was stirred for 20 min, then was added benzyl bromide(Aldrich, 6.2 mL, 52 mmol). After stirred for 3 h, the mixture wasdiluted with 2N HCl, extracted 3× with EtOAc (200 mL). The organiclayers were combined and washed twice with a brine solution (200 mL),dried over Na₂SO₄, and concentrated under vacuum. The residue waschromatographed (40%-60% CH₂Cl₂/hexanes) to yield 12.82 g (92%) ofproduct. ¹H NMR (400 MHz, DMSO) δ 7.87 (dd, J=8.1, 1.3 Hz, 1H), 7.76(dd, J=8.0, 1.3 Hz, 1H), 7.59 (t, J=8.1 Hz, 1H) 7.24-7.18 (m, 3H),7.10-7.06 (m, 2H), 4.15 (s, 2H).

Example 204

2-Benzylsulfanyl-3-chloro-phenylamine (204)

2-Benzylsulfanyl-3-chloro-phenylamine (204) was synthesized from benzyl2-chloro-6-nitrobenzenethiol ether (203, 20.0 g, 71.6 mmol) in a similarmanner as described in Examples 16-23 (Method A). ¹H NMR (400 MHz, DMSO)δ 7.27-7.18 (m, 5H), 7.00 (t, J=8.0 Hz, 1H), 6.65 (dd, J=8.0, 1.1 Hz,1H), 6.63 (dd, J=8.0, 1.1 Hz, 1H), 3.91 (s, 2H). The product was useddirectly for the next reaction as in Example 205.

Example 205

2-Amino-6-chlorobenzenethiol hydrochloride (205)

To a solution of 2-benzylsulfanyl-3-chloro-phenylamine (204) in 140 mLof benzene at 0° C. was added AlCl₃ (Aldrich, 23.8 g, 179 mmol) inportion. The mixture turned to purple. After stirred at ambienttemperature overnight, the mixture was poured to ice and EtOAc andstirred for 20 min. The mixture was extracted 3× with EtOAc (500 mL).The organic layers were washed twice with a brine solution (400 mL),dried over Na₂SO₄, and concentrated under vacuum. The crude product wastreated with 145 mL of 1N HCl in ether. The product (13.6 g) wascollected by filtration and washed with hexanes. ¹H NMR (400 MHz, DMSO)δ 7.05 (t, J=8.2 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 6.61 (d, J=7.8 Hz,1H).

Example 206

2-Amino-5-methyl-benzenethiol (206)

6-methyl-2-aminobenzothiazole (5 g) was suspended in a solution of KOH(25 g) in water (50 mL) and heated to reflux overnight. After cooling toambient temperature, the solution as adjusted to pH 6 with acetic acid.The thick precipitate was collected by filtration and rinsed with water.The residue was dissolved in methylene chloride, dried over magnesiumsulfate and concentrated to provide a yellow solid (4.08 g) containingthe desired 2-amino-5-methyl-benzenethiol. (88% purity). 1H NMR(d6-DMSO) 6.982 (d, J=2 Hz, 1H); 6.744 (dd, J=8, 2 Hz, 1H); 6.605 (d,J=8.4 Hz, 1H); 4.885 (br s, 2H); 3.32 (s, 1H); 2.103 (s, 3H). MS (EI):m/z 138 (M−H)

TABLE 9

Compound X 207 6-Cl 208 7-Cl 209 6-Me

The compounds of Table 9 were prepared using the method of Example 8.

Example 207 6-Chloro-2-(2,6-dichloro-4-nitro-benzyl)-benzothiazole (207)

¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 8.23 (d, J=2.1 Hz, 1H), 7.90(d, J=8.7 Hz, 1H), 7.50 (dd, J=8.7, 2.1 Hz, 1H), 4.87 (s, 2H). MS (EI):m/z 373 (M+H).

Example 208 7-Chloro-2-(2,6-dichloro-4-nitro-benzyl)-benzothiazole (208)

¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 7.91 (dd, J=7.8, 1.0 Hz, 1H),7.56 (t, J=7.7 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 4.92 (s, 2H). MS (EI):m/z 373 (M+H).

Example 209 2-(2,6-Dichloro-4-nitro-benzyl)-6-methyl-benzothiazole (209)

1H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 2H), 7.84 (br s, 1H), 7.76 (d,J=8.3 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 4.84 (s, 2H). MS (EI): m/z 353(M+H).

TABLE 10

Compound X 210 6-Cl 211 7-Cl 212 6-Me

The compounds of Table 10 were prepared using Method A described inExamples 16-23.

Example 2103,5-Dichloro-4-(6-chloro-benzothiazol-2-ylmethyl)-phenylamine (210)

¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (t, J=1.8 Hz, 1H), 7.92 (dd, J=8.7, 1.4Hz, 1H), 7.50 (dt, J=8.7, 2.0 Hz, 1H), 6.69 (s, 2H), 5.79 (s, 2H), 4.50(s, 2H). MS (EI): m/z 343 (M+H).

Example 2113,5-Dichloro-4-(7-chloro-benzothiazol-2-ylmethyl)-phenylamine (211)

¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (t, J=6.8 Hz, 1H), 7.92 (m, 2H), 6.70(s, 2H), 5.82 (s, 2H), 4.54 (s, 2H). MS (EI): m/z 343 (M+H).

Example 2123,5-Dichloro-4-(6-methyl-benzothiazol-2-ylmethyl)-phenylamine (212)

¹H NMR (400 MHz, DMSO-d₆) δ 7.82-7.75 (m, 2H), 7.28 (dd, J=8.3, 1.5 Hz,1H), 6.68 (s, 2H), 5.76 (s, 2H), 4.48 (s, 2H), 2.40 (s, 3H). MS (EI):m/z 323 (M+H).

Examples 213-220

The compounds of Table 11 were prepared from compounds in Table 10 andthe corresponding arylsulfonyl chloride using Method D described inExamples 70-91.

TABLE 11

Compound X A B 213 6-Cl CF₃ H 214 6-Cl Cl H 215 6-Cl Cl Me 216 7-Cl CF₃H 217 7-Cl Cl H 218 6-Me CF₃ H 219 6-Me Cl H 220 6-Me Cl Me

Example 2132-Chloro-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-ylmethyl)-phenyl]4-trifluoromethyl-benzenesulfonamide(213)

¹H NMR (400 MHz, DMSO-d₆) δ 11.55 (br s, 1H), 8.35 (d, J=8.2 Hz, 1H),8.19 (s, 1H), 8.15 (t, J=1.9 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.89 (d,J=8.7 Hz, 1H), 7.49 (dt, 8.7, 1.9 Hz, 1H), 7.23 (s, 2H), 4.60 (s, 2H).MS (EI): m/z 583 (M−H).

Example 2142,4-Dichloro-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide(214)

¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (br s, 1H), 8.18-8.12 (m, 2H), 7.93(t, J=1.7 Hz, 1H), 7.90 (dd, J=8.7, 1.1 Hz, 1H), 7.69 (dt, J=8.6, 1.7Hz, 1H), 7.49 (dt, J=8.7, 1.7 Hz, 1H), 7.20 (s, 2H), 4.60 (s, 2H). MS(EI): m/z 549 (M−H).

Example 2152,4-Dichloro-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-ylmethyl)-phenyl]-5-methyl-benzenesulfonamide(215)

¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (br s, 1H), 8.18-8.15 (m, 2H), 7.90(dd, J=8.7, 1.7 Hz, 1H), 7.87 (d, J=1.7 Hz, 1H), 7.49 (dt, J=8.7, 2.0Hz, 1H), 7.21 (s, 2H), 4.60 (s, 2H), 2.39 (s, 3H). MS (EI): m/z 563(M−H).

Example 2162-Chloro-N-[3,5-dichloro-4-(7-chloro-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(216)

¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (br s, 1H), 8.35 (d, J=8.3 Hz, 1H),8.19 (s, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.90 (dd, J=7.2, 1.5 Hz, 1H),7.58-7.50 (m, 2H), 7.23 (s, 2H), 4.64 (s, 2H). MS (EI): m/z 583 (M−H).

Example 2172,4-Dichloro-N-[3,5-dichloro-4-(7-chloro-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide(217)

¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (br s, 1H), 8.14 (d, J=8.6 Hz, 1H),7.95-7.90 (m, 2H), 7.69 (dd, J=8.6, 2.0 Hz, 1H), 7.58-7.48 (m, 2H), 7.20(s, 2H), 4.64 (s, 2H). MS (EI): m/z 549 (M−H).

Example 2182-Chloro-N-[3,5-dichloro-4-(6-methyl-benzothiazol-2-ylmethyl)-phenyl]4-trifluoromethyl-benzenesulfonamide(218)

¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (br s, 1H), 8.35 (d, J=8.3 Hz, 1H),8.18 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.78-7.70 (m, 2H), 7.26 (d,J=8.8.4 Hz, 1H), 7.22 (s, 2H), 4.56 (s, 2H), 2.39 (s, 3H). MS (EI): m/z563 (M−H).

Example 2192,4-Dichloro-N-[3,5-dichloro-4-(6-methyl-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide(219)

¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (br s, 1H), 8.14 (d, J=8.6 Hz, 1H),7.93 (d, J=2.1 Hz, 1H), 7.79-7.74 (m, 2H), 7.69 (dd, J=8.6, 2.1 Hz, 1H),7.32 (dd, J=8.5, 2.0 Hz, 1H), 7.20 (s, 2H), 4.56 (s, 2H), 2.40 (s, 3H).MS (EI): m/z 529 (M−H).

Example 2202,4-Dichloro-N-[3,5-dichloro-4-(6-methyl-benzothiazol-2-ylmethyl)-phenyl]-5-methyl-benzenesulfonamide(220)

¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (br s, 1H), 8.16 (s, 1H), 7.87 (s,1H), 7.80-7.74 (m, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.21 (s, 2H), 4.56 (s,2H), 2.40 (s, 3H), 2.38 (s, 3H). MS (EI): m/z 543 (M−H).

Example 221

Quinolin-2-yl-acetonitrile (221)

To a suspension of 2-Chloromethyl-quinoline hydrochloride (TCI, 4.28 g,20 mmol) in 50 mL of EtOH was added a solution of NaHCO₃ (EM, 3.36 g, 40mmol) in 30 mL of H₂O. The mixture was stirred for 15 min, then wasadded KI (Aldrich, 4.5 g, 30 mmol) and KCN (Acros, 1.95 g, 30 mmol) andthe resulting mixture was refluxed for 4 h. after cooled to roomtemperature, EtOH was removed under reduced pressure. The residue wasextracted 3× with EtOAc (200 mL). The organic layers were combined andwashed twice with a brine solution (200 mL), dried over Na₂SO₄, andconcentrated under vacuum. The residue was chromatographed (30%EtOAc/hexanes) to yield 2.76 g (82%) of product. ¹H NMR (400 MHz,DMSO-d₆) δ 8.42 (d, J=8.4 Hz, 1H), 8.05-7.97 (m, 2H), 7.85-7.76 (m, 1H),7.67-7.60 (m, 1H), 7.54 (d, J=8.5 Hz, 1H), 4.45 (s, 2H). MS (EI): m/z169 (M+H).

Example 222

2-(2,6-Dichloro-4-nitro-benzyl)-quinoline (222)

To a solution of quinolin-2-yl-acetonitrile (Example 221, 2.76 g, 16.4mmol) in 30 mL of DMF, was added NaH (Aldrich, 1.44 g, 60%, 36.1 mmol)and the mixture was stirred for 15 min. To the above mixture was added3,4,5-trichloronitrobenzene (Acros, 3.71 g, 16.4 mmol), and theresulting mixture was stirred overnight (16 h). Poured to 2N HCl, thecrude product (5.50 g) was collected by filtration followed by washingwith water. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 7.75 (d, J=9.6Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.50-7.42 (m, 1H), 7.35 (d, J=8.2 Hz,1H), 7.22-7.14 (m, 2H).

The above crude product (3.6 g) was suspended in a mixture of 50 mL con.HCl and 20 mL of AcOH and the resulting mixture was refluxed overnight(18 h). After cooled to room temperature, the mixture was brought to pH8 with con. NH₄OH, and then extracted 3× with EtOAc (200 mL). Theorganic layers were combined and washed twice with a brine solution (200mL), dried over Na₂SO₄, and concentrated under vacuum. The residue waschromatographed (10%-15% EtOAc/hexanes) to yield 2.66 g of product. ¹HNMR (400 MHz, DMSO-d₆) δ 8.39 (s, 2H), 8.33 (d, J=8.5 Hz, 1H), 7.95 (d,J=7.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.69 (td, J=8.1, 1.3 Hz, 1H),7.56 (td, J=8.0, 1.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 4.74 (s, 2H). MS(EI): m/z 333 (M+H).

Example 223

3,5-Dichloro-4-quinolin-2-ylmethyl-phenylamine (223)

3,5-Dichloro-4-quinolin-2-ylmethyl-phenylamine (223) was synthesized(84%) from 2-(2,6-Dichloro-4-nitro-benzyl)-quinoline (222) in a similarmanner as described in Examples 16-23 (Method A). ¹H NMR (400 MHz,DMSO-d₆) δ 8.24 (d, J=8.5 Hz, 1H), 7.91 (m, 2H), 7.72 (td, J=7.8, 1.4Hz, 1H), 7.54 (td, J=7.8, 1.0 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.69 (s,2H), 5.67 (s, 2H), 4.41 (s, 2H). MS (EI): m/z 303 (M+H).

Example 224

2-Chloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-4-trifluoromethyl-benzenesulfonamide(224)

2-Chloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)₄-trifluoromethyl-benzenesulfonamidewas synthesized (84%) from3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223),2-chloro-4-trifluromethylbenzenesulfonyl chloride (Maybridge) andpyridine (EM) in a similar manner as described in Examples 70-91. ¹H NMR(400 MHz, DMSO-d₆) δ 11.45 (br s, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.24 (d,J=8.5 Hz, 1H), 8.19 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.0 Hz,1H), 7.76 (d, J=8.3 Hz, 1H), 7.67 (td, J=7.8, 1.3 Hz, 1H), 7.54 (td,J=7.8, 1.0 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.22 (s, 2H), 4.48 (s, 2H).MS (EI): m/z 543 (M−H).

Example 225

2,4-Dichloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-benzenesulfonamide (225)

2,4-Dichloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-benzenesulfonamidewas synthesized (76%) from3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223),2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.29 (br s, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.94(d, J=2.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H),7.70-7.65 (m, 2H), 7.54 (t, J=7.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.20(s, 2H), 4.48 (s, 2H). MS (EI): m/z 509 (M−H).

Example 226

2,4-Dichloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-5-methyl-benzenesulfonamide(226)

2,4-Dichloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-5-methyl-benzenesulfonamidewas synthesized (76%) from3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223),2,4-dichloro-5-methylbenzenesulfonyl chloride (Maybridge) and pyridine(EM) in a similar manner as described in Examples 70-91. ¹H NMR (400MHz, DMSO-d₆) δ 11.22 (br s, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.15 (s, 1H),7.91 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.69 (t,J=7.1 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.21 (s,2H), 4.48 (s, 2H), 2.39 (s, 3H). MS (EI): m/z 523 (M−H).

Example 227

Quinolin-3-yl-methanol (227)

To a suspension of quinoline-3-carboxylic acid (Aldrich, 4.85 g, 28.0mmol) in 60 mL of 10% MeOH/THF, was added dropwise a solution of 2M(trimethylsilyl)diazomethane (Aldrich, 21 mL, 42 mmol) in hexanes. Themixture was stirred at ambient temperature for 4 h. Removal of thesolvent under reduced pressure gave 5.03 g of crude product, which wasused directly for the next reaction.

To a solution of the above product in 100 mL of THF at −78° C. was addeda solution of 1M LiAlH₄ (Aldrich, 40.3 mL, 40.3 mmol) in THF. Themixture was stirred at −78° C. for 30 min, then was allowed to slowlywarm up to 0° C. Cooled to −78° C., to the mixture was added 1 mL ofEtOAc, 1 mL of H₂O, 1 mL of 2N NaOH and 1 mL of H₂O. The mixture waswarmed up to room temperature, diluted with EtOAc, dried over Na₂SO₄,and concentrated under vacuum. The residue was chromatographed (3%MeOH/CH₂Cl₂) to yield 2.12 g (48%) of product. ¹H NMR (400 MHz, DMSO-d₆)δ 8.87 (d, J=2.1 Hz, 1H), 8.24 (s, 1H), 8.03-7.97 (m, 2H), 7.75-7.70 (m,1H), 7.62-7.58 (m, 1H), 5.48 (t, J=5.5 Hz, 1H), 4.73 (d, J=5.2 Hz, 2H).MS (EI): m/z 160 (M+H).

Example 228

Quinolin-3-yl-acetonitrile (228)

A solution of quinolin-3-yl-methanol (227, 3.1 g, 19.5 mmol) and thionylchloride (Aldrich, 16.5 mL, 195 mmol) in 50 mL of benzene was refluxedfor 3 h. After cooled to room temperature, the solvent was removed underreduced pressure to dryness. This crude product was used directly in thenext reaction. ¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.82 (s, 1H),8.21 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.97 (t, J=7.4 Hz, 1H),7.81 (t, J=7.5 Hz, 1H), 5.09 (s, 2H). MS (EI): m/z 178 (M+H).Quinolin-3-yl-acetonitrile was synthesized from the above crude product,KCN, NaHCO₃ and KI in similar manner as described in Example 221. ¹H NMR(400 MHz, DMSO-d₆) δ 8.87 (d, J=2.0 Hz, 1H), 8.36 (s, 1H), 8.05 (d,J=8.3 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.79 (t, J=7.3 Hz, 1H), 7.65 (t,J=7.8 Hz, 1H), 4.31 (s, 2H). MS (EI): m/z 169 (M+H).

Example 229

3-(2,6-Dichloro-4-nitro-benzyl)-quinoline (229)

3-(2,6-Dichloro-4-nitro-benzyl)-quinoline was synthesized (71%) fromquinolin-3-yl-acetonitrile (228, 1.41 g, 8.4 mmol),3,4,5-trichloronitrobenzene (Acros, 1.90 g, 8.4 mmol) and NaH (Aldrich,740 mg, 60%, 18.5 mmol) in a similar manner in two steps as described inExample 222. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.42 (d, J=0.9Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.92-7,86 (m, 2H), 7.72 (td, J=7.0, 1.3Hz, 1H), 7.58 (td, J=8.0, 1.0 Hz, 1H), 4.59 (s, 2H). MS (EI): m/z 333(M+H).

Example 230

3,5-Dichloro-4-quinolin-3-ylmethyl-phenylamine (230)

3,5-Dichloro-4-quinolin-3-ylmethyl-phenylamine (230) was synthesized(84%) from 3-(2,6-dichloro-4-nitro-benzyl)-quinoline (229) in a similarmanner as described in Examples 16-23 (Method A). ¹H NMR (400 MHz,DMSO-d₆) δ 8.80 (d, J=2.2 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.91 (d,J=8.0 Hz, 1H), 7.86 (s, 1H), 7.70 (td, J=7.8, 1.0 Hz, 1H), 7.13 (t,J=7.5 Hz, 1H), 6.70 (s, 2H), 5.68 (s, 2H), 4.27 (s, 2H). MS (EI): m/z303 (M+H).

Example 231

2-Chloro-N-(3,5-dichloro-4-quinolin-3-ylmethyl-phenyl)-4-trifluoromethyl-benzenesulfonamide(231)

2-Chloro-N-(3,5-dichloro-4-quinolin-3-ylmethyl-phenyl)₄-trifluoromethyl-benzenesulfonamidewas synthesized (80%) from3,5-dichloro-4-quinolin-3-ylmethyl-phenylamine (230),2-chloro-4-trifluromethylbenzenesulfonyl chloride (Maybridge) andpyridine (EM) in a similar manner as described in Examples 70-91. ¹H NMR(400 MHz, DMSO-d₆) δ 11.49 (br s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.34 (d,J=8.3 Hz, 1H), 8.19 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.96 (d, J=7.7 Hz,1H), 7.86 (d, J=8.0 Hz, 1H), 781 (s, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.23(t, J=7.5 Hz, 1H), 7.24 (s, 2H), 4.34 (s, 2H). MS (EI): m/z 543 (M−H).

Example 232

2,4-Dichloro-N-(3,5-dichloro-4-quinolin-3-ylmethyl-phenyl)-benzenesulfonamide (232)

2,4-Dichloro-N-(3,5-dichloro-4-quinolin-3-ylmethyl-phenyl)-benzenesulfonamidewas synthesized (63%) from3,5-dichloro-4-quinolin-3-ylmethyl-phenylamine (230),2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.34 (br s, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.97(d, J=8.6 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.80(s, 1H), 7.73-7.68 (m, 2H), 7.58 (t, J=7.5 Hz, 1H), 7.21 (s, 2H), 4.34(s, 2H). MS (EI): m/z 509 (M−H).

Example 233

Isoquinolin-3-yl-methanol (233)

Isoquinolin-3-yl-methanol was synthesized (32%) fromisoquinoline-3-carboxylic acid (TCI, 5.0 g, 28.9 mmol) in a similarmanner as described in Example 227. ¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (s,1H), 8.10 (d, J=8.2 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.83 (s, 1H), 7.75(t, J=7.5 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 5.50 (td, J=5.7, 0.7 Hz, 1H),4.73 (d, J=5.7 Hz, 2H). MS (EI): m/z 160 (M+H).

Example 234

Isoquinolin-3-yl-acetonitrile (234)

Isoquinolin-3-yl-acetonitrile was synthesized (80%) fromisoquinolin-3-yl-methanol (233) in a similar manner as described inExample 228. ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.25 (d, J=8.1Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.86 (s, 1H), 7.81 (td, J=7.6, 1.0 Hz,1H), 7.70 (td, J=7.8, 0.6 Hz, 1H), 4.32 (s, 2H). MS (EI): m/z 169 (M+H).

Example 235

3-(2,6-Dichloro-4-nitro-benzyl)-isoquinoline (235)

3-(2,6-Dichloro-4-nitro-benzyl)-isoquinoline was synthesized (79%) fromisoquinolin-3-yl-acetonitrile (234, 1.22 g, 7.26 mmol),3,4,5-trichloronitrobenzene (Acros, 1.64 g, 7.26 mmol) and NaH (Aldrich,640 mg, 60%, 16.0 mmol) in a similar manner in two steps as described inExample 222. ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.38 (s, 2H),8.07 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H),7.64 (t, J=7.5 Hz, 1H), 7.57 (s, 1H), 4.68 (s, 2H). MS (EI): m/z 333(M+H).

Example 236

3,5-Dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236)

3,5-Dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236) was synthesized(84%) from 3-(2,6-dichloro-4-nitro-benzyl)-isoquinoline (235) in asimilar manner as described in Examples 16-23 (Method A). ¹H NMR (400MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.2 Hz,1H), 7.70 (t, J=7.5 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.22 (s, 1H), 6.70(s, 2H), 5.65 (s, 2H), 4.37 (s, 2H). MS (EI): m/z 303 (M+H).

Example 237

2-Chloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)4-trifluoromethyl-benzenesulfonamide(237)

2-Chloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)₄-trifluoromethyl-benzenesulfonamidewas synthesized (65%) from3,5-dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236),2-chloro-4-trifluromethyl-benzenesulfonyl chloride (Maybridge) andpyridine (EM) in a similar manner as described in Examples 70-91. ¹H NMR(400 MHz, DMSO-d₆) δ 11.46 (br s, 1H), 9.19 (s, 1H), 8.35 (d, J=8.2 Hz,1H), 8.19 (d, J=1.1 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.99 (dd, J=8.3,1.2 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.71 (td, J=7.5, 1.0 Hz, 1H), 7.60(td, J=7.5, 0.8 Hz, 1H), 7.22 (s, 2H), 4.42 (s, 2H). MS (EI): m/z 543(M−H).

Example 238

2,4-Dichloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)-benzenesulfonamide (238)

2,4-Dichloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)-benzenesulfonamidewas synthesized (63%) from3,5-dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236),2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.30 (br s, 1H), 9.19 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.74-7.68 (m,2H), 7.60 (td, J=7.5, 1.0 Hz, 1H), 7.31 (s, 1H), 7.20 (s, 2H), 4.42 (s,2H). MS (EI): m/z 509 (M−H).

Example 250

3-Chloro-5-hydroxy-benzoic acid (250)

To a solution of 3,5-dichlorobenzoic acid (Aldrich, 19.2 g, 100 mmol) inHMPA was added NaOMe (Aldrich, 27.0 g, 500 mmol). The mixture was heatedat 150° C. for 2 d. After cooled to room temperature, the reactionmixture was poured to ice/water, acidified to pH 1 with con. HCl,extracted 3× with EtOAc (400 mL). The organic layers were washed twicewith a brine solution (300 mL), dried over Na₂SO₄. Removal of thesolvent under reduced pressure gave a crude product.

To a stirred solution of the above product in 100 mL of AcOH at 50° C.was added 140 mL of 48% HBr (Aldrich). The mixture was then refluxedovernight. After cooled to room temperature, the reaction mixture waspoured to ice/water. The desired product was collected by filtrationfollowed by washing with water. ¹H NMR (400 MHz, DMSO₆) δ 13.3 (br s,1H), 10.31 (s, 1H), 7.33 (t, J=1.6 Hz, 1H), 7.29 (dd, J=2.2, 1.5 Hz,1H), 7.04 (t, J=2.1 Hz, 1H).

Example 251

3-Amino-4-chloro-benzonitrile (251)

3-Amino-4-chloro-benzonitrile was synthesized (98%) from4-chloro-3-nitro-benzonitrile (Fluka) in a similar manner as describedin Examples 16-23 (Method A). ¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (d, J=8.1Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.93 (dd, J=8.2, 2.0 Hz, 1H), 5.89 (s,2H).

Example 252

2-Mercapto-benzothiazole-5-carbonitrile (252)

To a solution of 3-amino-4-chloro-benzonitrile (Example 251, 9.0 g, 59mmol) in 90 mL of DMF was added O-ethylxanthic acid potassium salt(Aldrich, 21.23 g, 133 mmol). The mixture was heated to 115° C. for 4 h.After cooled to room temperature, the mixture was diluted with ice/waterand was acidified to pH 2 with 2N HCl. Filtration followed by washingwith water gave a crude product, which was recrystalized from EtOH/waterto give 5.6 g (49%) of product. ¹H NMR (400 MHz, DMSO-d₆) δ 14.10 (br s,1H), 7.90 (d, J=8.3 Hz, 1H), 7.69 (dd, J=8.3, 1.1 Hz, 1H), 7.60 (s, 1H).MS (EI): m/z 191 (M−H).

Examples 253-262

The compounds in Table 12 were prepared using the method described inExample 253 (Method A in Table 12) or Example 255 (Method B in Table 12)below, as indicated.

TABLE 12

Compound X Method 253 5-Cl A 254 5-CN A 255 4-Cl B 256 4-Me B 257 4-OMeB 258 6-Me B 259 6-Cl B 260 6-F B 261 6-OMe B 262 6-COOEt B

Example 253 2,5-Dichloro-benzothiazole (253)

To 5-chloro-benzothiazole-2-thiol (Aldrich, 10.09 g, 50 mmol) was addedSO₂Cl₂, and the mixture was stirred at ambient temperature for 1 h thenheated at 60° C. for 30 min. After cooled to room temperature, themixture was poured to ice/water and stirred for 30 min. The desiredproduct was collected by filtration followed by washing with water. ¹HNMR (400 MHz, DMSO-d₆) δ 8.16 (d, J=8.7 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H),7.58 (dd, J=8.7, 2.1 Hz, 1H).

Example 254 2-Chloro-benzothiazole-5-carbonitrile (254)

2-Chloro-benzothiazole-5-carbonitrile was synthesized from2-mercapto-benzothiazole-5-carbonitrile (252) in a similar manner asdescribed in Example 253. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, J=1.5 Hz,1H), 8.35 (d, J=8.4 Hz, 1H), 7.92 (dd, J=8.4, 1.5 Hz, 1H).

Example 255 2,4-Dichloro-benzothiazole (255)

Anhydrous CuCl₂ (Aldrich, 4.37 g, 32.5 mmol), t-butyl nitrite (Aldrich,4.83 mL, 40.6 mmol) and anhydrous acetonitrile (EM, 50 mL) were added toa 3-necked round-bottomed flask equipped with a reflux condenser, anadditional funnel and a gas outlet tube. The mixture was warmed to 65°C. and a suspension of 2-amino-4-chlorobenzothiazole in 50 mL ofacetonitrile. During the addition, the reaction mixture tuned to blackand gas evolved. After gas evolution is complete, the reaction wasallowed to reach room temperature. The reaction mixture was poured to300 mL of 20% aqueous HCl, extracted 3× with EtOAc (400 mL). The organiclayers were washed twice with a brine solution (300 mL), dried overNa₂SO₄ and concentrated. The residue was purified by chromatography with60% CH₂Cl₂/hexanes to give 4.8 g of product. ¹H NMR (400 MHz, DMSO-d₆) δ8.10 (dd, J=8.1, 1.0 Hz, 1H), 7.68 (dd, J=7.9, 1.0 Hz, 1H), 7.51 (t,J=8.0 Hz, 1H).

Example 256 2-Chloro-4-methyl-benzothiazole (256)

2-Chloro-4-methyl-benzothiazole was synthesized from2-amino-4-methyl-benzothiazole (Aldrich) in a similar manner asdescribed in Example 255. ¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (dd, J=7.7,1.5 Hz, 1H), 7.42-7.38 (m, 2H), 2.60 (s, 3H).

Example 257 2-Chloro-4-methoxy-benzothiazole (257)

2-Chloro-4-methoxy-benzothiazole was synthesized from2-amino-4-methoxy-benzothiazole (Aldrich) in a similar manner asdescribed in Example 255. ¹H NMR (400 MHz, DMSO-d₆) δ 7.62 (dd, J=8.2,0.7 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 3.94 (s,3H).

Example 258 2-Chloro-6-methyl-benzothiazole (258)

2-Chloro-6-methyl-benzothiazole was synthesized from2-amino-6-methyl-benzothiazole (Aldrich) in a similar manner asdescribed in Example 255. ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=0.7 Hz,1H), 7.84 (t, J=8.3 Hz, 1H), 7.38 (dd, J=8.3, 1.3 Hz, 1H), 2.73 (s, 3H).

Example 259 2,6-Dichloro-benzothiazole (259)

2,6-Dichloro-benzothiazole was synthesized from2-amino-6-chloro-benzothiazole (Aldrich) in a similar manner asdescribed in Example 255. ¹H NMR (400 MHz, DMSO-d₆) δ 7.03 (d, J=2.2 Hz,1H), 7.98 (d, J=8.7 Hz, 1H), 7.60 (dd, J=8.7, 2.2 Hz, 1H).

Example 260 2-Chloro-6-fluoro-benzothiazole (260)

2-Chloro-6-fluoro-benzothiazole was synthesized from2-amino-6-fluoro-benzothiazole (Aldrich) in a similar manner asdescribed in Example 255. ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (dd, J=8.9,2.1 Hz, 1H), 8.01 (dd, J=8.7, 5.0 Hz, 1H), 7.45 (td, J=8.1, 2.7 Hz, 1H).

Example 261 2-Chloro-6-methoxy-benzothiazole (261)

2-Chloro-6-methoxy-benzothiazole was synthesized from2-amino-6-methoxy-benzothiazole (Aldrich) in a similar manner asdescribed in Example 255. ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (d, J=8.6 Hz,1H), 7.69 (s, 1H), 7.14 (d, J=8.1 Hz, 1H), 3.82 (s, 3H).

Example 262 2-Chloro-benzothiazole-6-carboxylic acid ethyl ester (262)

2-Chlorobenzothiazole-6-carboxylic acid ethyl ester was synthesized from2-amino-benzothiazole-6-carboxylic acid ethyl ester (Astatech) in asimilar manner as described in Example 255. ¹H NMR (400 MHz, DMSO-d₆) δ8.80 (d, J=1.0 Hz, 1H), 8.09 (dd, J=8.6, 1.6 Hz, 1H), 8.06 (d, J=8.5 Hz,1H), 4.35 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).

Example 263 [3-Chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenyl]-carbamicacid tert-butyl ester (263)

To a solution of 3-Chloro-5-hydroxy-benzoic acid (Example 250, 1.73 g,10 mmol) in DMF was added NaH (Aldrich, 840 mg, 60%, 21 mmol). Themixture was stirred for 10 min, then 2,5-dichlorobenzothiazole (Example253, 2.03 g, 10 mmol) was added. The mixture was heated at 60° C. tillthere is no starting material remained by TLC. After cooled to roomtemperature, the mixture was poured to ice/1N HCl, extracted 3× withEtOAc (100 mL). The organic layers were washed twice with a brinesolution (100 mL), dried over Na₂SO₄ and concentrated. The resultingmaterial was used directly in the next reaction.

To a solution of the above product in 20 mL of tert-butanol was addeddiphenylphosphoryl azide (Aldrich, 2.16 mL, 10 mmol) and triethylamine(Aldrich, 1.4 mL, 10 mmol). The mixture was refluxed overnight, cooledto room temperature and concentrated to dryness under reduced pressure.The residue was purified by chromatography with 50%-70% CH₂Cl₂/hexanesto give 2.10 g of product. ¹H NMR (400 MHz, DMSO-d6) δ 9.85 (br s, 1H)8.01 (d, J=8.6 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.53 (b s, 1H), 7.50 (t,J=2.0 Hz, 1H), 7.42 (dd, J=8.6, 2.1 Hz, 1H), 7.26 (t, J=2.0 Hz, 1H),1.47 (s, 9H). MS (EI): m/z 411 (M+H).

TABLE 13

Compound X 263 5-Cl 264 5-CN 265 4-Cl 266 4-Me 267 4-OMe 268 6-Me 2696-Cl 270 6-F 271 6-OMe 272 6-COOEtThe compounds of Table 13 were prepared in a similar manner as describedin Example 263.

Example 264 [3-Chloro-5-(5-cyano-benzothiazol-2-yloxy)-phenyl]-carbamicacid tert-butyl ester (264)

¹H NMR (400 MHz, DMSO-d₆) δ 9.87 (br s, 1H), 8.26 (d, J=1.5 Hz, 1H),8.22 (d, J=8.3 Hz, 1H), 7.77 (dd, J=8.3, 1.6 Hz, 1H), 7.53 (t, J=1.8 Hz,1H), 7.51 (t, J=1.9 Hz, 1H), 7.29 (t, J=2.0 Hz, 1H), 1.47 (s, 9H). MS(EI): m/z 400 (M−H).

Example 265 [3-Chloro-5-(4-chloro-benzothiazol-2-yloxy)-phenyl]-carbamicacid tert-butyl ester (265)

¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (br s, 1H), 7.95 (dd, J=8.0, 1.0 Hz,1H), 7.56 (d, J=8.0, 1.0 Hz, 1H), 7.52 (t, J=2.0 Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.35-7.31 (m, 2H), 1.47 (s, 9H). MS (EI): m/z 355 (M⁺—C₄H₈).

Example 266 [3-Chloro-5-(4-methyl-benzothiazol-2-yloxy)-phenyl]-carbamicacid tert-butyl ester (266)

¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (br s, 1H), 7.76 (dd, J=7.2, 1.6 Hz,1H), 7.56 (t, J=1.8 Hz, 1H), 7.53 (t, J=1.7 Hz, 1H), 7.30-7.22 (m, 3H),2.49 (s, 3H), 1.47 (s, 9H). MS (EI): m/z 389 (M−H).

Example 267[3-Chloro-5-(4-methoxy-benzothiazol-2-yloxy)-phenyl]-carbamic acidtert-butyl ester (267)

¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (br s, 1H), 7.52-7.50 (m, 2H), 7.45 (t,J=1.9 Hz, 1H), 7.31 (t, J=8.1 Hz, 1H), 7.21 (t, J=2.0 Hz, 1H), 7.03 (d,J=8.1 Hz, 1H), 3.86 (s, 3H), 1.47 (s, 9H). MS (EI): m/z 407 (M+H).

Example 268 [3-Chloro-5-(6-methyl-benzothiazol-2-yloxy)-phenyl]-carbamicacid tert-butyl ester (268)

¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (br s, 1H), 7.76 (s, 1H), 7.60 (d,J=8.2 Hz, 1H), 7.52 (br s, 1H), 7.47 (t, J=1.9 Hz, 1H), 7.26 (dd, J=8.2,1.2 Hz, 1H), 7.22 (t, J=2.0 Hz 1H), 2.40 (s, 3H), 1.47 (s, 9H). MS (EI):m/z 389 (M−H).

Example 269 [3-Chloro-5-(6-chloro-benzothiazol-2-yloxy)-phenyl]-carbamicacid tert-butyl ester (269)

¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (br s, 1H), 8.14 (d, J=2.1 Hz, 1H),7.73 (d, J=8.6 Hz, 1H), 7.53-7.45 (m, 3H), 7.26 (t, J=2.0 Hz, 1H), 1.47(s, 9H). MS (EI): m/z 355 (M⁺—C₄H₈).

Example 270 [3-Chloro-5-(6-fluoro-benzothiazol-2-yloxy)-phenyl]-carbamicacid tert-butyl ester (270)

¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (br s, 1H), 7.92 (dd, J=8.7, 2.7 Hz,1H), 7.75 (dd, J=8.9, 4.8 Hz, 1H), 7.52 (br s, 1H), 7.49 (br s, 1H),7.31 (td, J=9.0, 2.7 Hz, 1H), 7.25 (t, J=2.0 Hz, 1H), 1.47 (s, 9H). MS(EI): m/z 355 (M⁺—C₄H₈).

Example 271[3-Chloro-5-(6-methoxy-benzothiazol-2-yloxy)-phenyl]-carbamic acidtert-butyl ester (271)

¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (br s, 1H), 7.62 (d, J=8.8 Hz, 1H),7.58 (d, J=2.5 Hz, 1H), 7.51 (br s, 1H), 7.45 (br s, 1H), 7.21 (t, J=2.0Hz, 1H), 7.03 (dd, J=8.9, 2.6 Hz, 1H), 3.79 (s, 3H), 1.47 (s, 9H). MS(EI): m/z 407 (M+H).

Example 2722-(3-tert-Butoxycarbonylamino-5-chloro-phenoxy)-benzothiazole-6-carboxylicacid ethyl ester (272)

¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (br s, 1H), 8.66 (d, J=1.6 Hz, 1H),8.01 (dd, J=8.5, 1.6 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.54 (br s, 1H),7.52 (br s, 1H), 7.30 (t, J=1.8 Hz, 1H), 4.34 (q, J=7.1 Hz, 1H), 1.47(s, 9H), 1.34 (t, J=7.1 Hz, 3H), MS (EI): m/z 393 (M⁺—C₄H₈).

Example 273 3-Chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenylamine (273)

To [3-chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenyl]-carbamic acidtert-butyl ester (263, 1.17 g, 2.85 mmol) was added trifluoroaceticacid. The mixture was stirred at ambient temperature for 5 h, at whichtime TLC showed there was no starting material remained. The mixture wasconcentrated to dryness under reduced pressure, dissolved in EtOAc. Theorganic solution was washed with 1N NaOH, washed twice with a brinesolution, dried over Na₂SO₄ and concentrated. The residue was purifiedby chromatography with CH₂Cl₂ to give 785 mg of product. ¹H NMR (400MHz, DMSO-d₆) δ 7.98 (d, J=8.6 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 6.62 (t,J=1.9 Hz, 1H), 6.58 (t, J=1.8 Hz, 1H), 6.50 (t, J=1.9 Hz, 1H), 5.81 (s,2H). MS (EI): m/z 311 (M+H).

Examples 274-282

The compounds in Table 14 were prepared from compounds in Table 13 in asimilar manner as described in Example 273 above.

TABLE 14

Compound X 273 5-Cl 274 5-CN 275 4-Cl 276 4-Me 277 4-OMe 278 6-Me 2796-Cl 280 6-F 281 6-OMe 282 6-COOEt

Example 274 2-(3-Amino-5-chloro-phenoxy)-benzothiazole-5-carbonitrile(274)

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=1.2 Hz, 1H), 7.82 (d, J=2.0 Hz,1H), 7.76 (dd, J=8.3, 1.6 Hz, 1H), 6.65 (t, J=2.0 Hz, 1H), 6.59 (t,J=1.9 Hz, 1H), 6.52 (t, J=2.0 Hz, 1H), 5.81 (s, 2H). MS (EI): m/z 302(M+H).

Example 275 3-Chloro-5-(4-chloro-benzothiazol-2-yloxy)-phenylamine (275)

¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (dd, J=8.0, 1.0 Hz, 1H), 7.54 (dd,J=7.9, 1.0 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 6.66 (t, J=2.0 Hz, 1H), 6.60(t, J=1.9 Hz, 1H), 6.52 (t, J=2.0 Hz, 1H), 5.76 (s, 2H). MS (EI): m/z311 (M+H).

Example 276 3-Chloro-5-(4-methyl-benzothiazol-2-yloxy)-phenylamine (276)

¹H NMR (400 MHz, DMSO-d₆) δ 7.74 (dd, J=7.5, 1.0 Hz, 1H), 7.27 (dd,J=7.3, 1.3 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 6.62 (t, J=2.0 Hz, 1H), 6.57(t, J=1.9 Hz, 1H), 6.51 (t, J=2.0 Hz, 1H), 5.82 (s, 2H), 2.50 (s, 3H).MS (EI): m/z 291 (M+H).

Example 277 3-Chloro-5-(4-methoxy-benzothiazol-2-yloxy)-phenylamine(277)

¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (dd, J=8.0, 0.9 Hz, 1H), 7.29 (t, J=8.1Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.57 (t, J=2.0 Hz, 1H), 6.56 (t, J=1.9Hz, 1H), 6.46 (t, J=2.0 Hz, 1H), 5.80 (s, 2H), 3.87 (s, 3H). MS (EI):m/z 307 (M+H).

Example 278 3-Chloro-5-(6-methyl-benzothiazol-2-yloxy)-phenylamine (278)

¹H NMR (400 MHz, DMSO-d₆) δ 7.73 (d, J=0.4 Hz, 1H), 7.60 (d, J=8.2 Hz,1H), 7.25 (dd, J=8.3, 1.6 Hz, 1H), 6.58 (t, J=2.0 Hz, 1H), 6.56 (t,J=1.9 Hz, 1H), 6.49 (t, J=2.0 Hz, 1H), 5.76 (s, 2H), 2.39 (s, 3H). MS(EI): m/z 291 (M+H).

Example 279 3-Chloro-5-(6-chloro-benzothiazol-2-yloxy)-phenylamine (279)

¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 7.72 (d, J=8.6 Hz,1H), 7.47 (dd, J=8.7, 2.2 Hz, 1H), 6.62 (t, J=2.0 Hz, 1H), 6.57 (t,J=1.8 Hz, 1H), 6.50 (t, J=2.0 Hz, 1H), 5.82 (s, 2H). MS (EI): m/z 311(M+H).

Example 280 3-Chloro-5-(6-fluoro-benzothiazol-2-yloxy)-phenylamine (280)

¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (dd, J=8.7, 2.7 Hz, 1H), 7.74 (dd,J=8.9, 4.9 Hz, 1H), 7.30 (td, J=9.0, 2.7 Hz, 1H), 6.60 (t, J=2.0 Hz,1H), 6.56 (t, J=1.9 Hz, 1H), 6.50 (t, J=2.0 Hz, 1H), 5.81 (s, 2H). MS(EI): m/z 295 (M+H).

Example 281 3-Chloro-5-(6-methoxy-benzothiazol-2-yloxy)-phenylamine(281)

¹H NMR (400 MHz, DMSO-d₆) δ 7.62 (d, J=8.9 Hz, 1H), 7.56 (dd, J=2.7 Hz,1H), 7.03 (dd, J=8.8, 2.6 Hz, 1H), 6.56 (t, J=2.0 Hz, 1H), 6.54 (t,J=1.8 Hz, 1H), 6.47 (t, J=2.0 Hz, 1H), 5.78 (s, 2H). MS (EI): m/z 307(M+H).

Example 282 2-(3-Amino-5-chloro-phenoxy)-benzothiazole-6-carboxylic acidethyl ester (282)

¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, J=1.6 Hz, 1H), 8.00 (dd, J=8.5, 1.8Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 6.65 (t, J=2.0 Hz, 1H), 6.59 (t, J=1.9Hz, 1H), 6.52 (t, J=2.0 Hz, 1H), 5.84 (s, 2H), 4.33 (q, J=7.1 Hz, 2H),1.33 (t, J=7.1 Hz, 3H). MS (EI): m/z 349 (M+H).

Example 282

The compounds in Table 15 were prepared from compounds in Table 14 andcorresponding arylsulfonyl chloride using the one of the methods ofExamples 70-91.

TABLE 15

Compound X A B 283 5-Cl CF₃ H 284 5-Cl Cl H 285 5-Cl Cl Me 286 5-CN CF₃H 287 5-CN Cl H 288 5-CN Cl Me 290 4-Cl CF₃ H 291 4-Cl Cl H 292 4-Cl ClMe 293 4-Me CF₃ H 294 4-Me Cl H 295 4-Me Cl Me 296 4-OMe CF₃ H 297 4-OMeCl H 298 4-OMe Cl Me 299 6-Me CF₃ H 300 6-Me Cl H 301 6-Me Cl Me 3026-Cl CF₃ H 303 6-Cl Cl H 304 6-F CF₃ H 305 6-F Cl H 306 6-F Cl Me 3076-OMe CF₃ H 308 6-OMe Cl H 309 6-OMe Cl Me 310 6-COOEt CF₃ H 311 6-COOEtCl H

Example 2832-Chloro-N-[3-chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(283)

¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 8.31 (d, J=8.5 Hz, 1H), 8.18(s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.76 (d, J=2.1Hz, 1H), 7.43 (dd, J=8.6, 2.1 Hz, 1H), 7.38 (t, J=1.9 Hz, 1H), 7.12-7.10(m, 2H). MS (EI): m/z 551 (M−H).

Example 2842,4-Dichloro-N-[3-chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(284)

¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.01(d, J=8.6 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.59(dd, J=8.6, 2.1 Hz, 1H), 7.43 (dd, J=8.6, 2.1 Hz, 1H), 7.36 (t, J=2.0Hz, 1H), 7.10-7.06 (m, 2H). MS (EI): m/z 517 (M−H).

Example 2852,4-Dichloro-N-[3-chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(285)

¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H), 8.11 (s, 1H), 8.00 (d, J=8.6Hz, 1H), 7.86 (s, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.43 (dd, J=8.6, 2.1 Hz,1H), 7.34 (t, J=2.0 Hz, 1H), 7.11-7.06 (m, 2H), 2.19 (s, 3H). MS (EI):m/z 531 (M−H).

Example 2862-Chloro-N-[3-chloro-5-(5-cyano-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(286)

¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (s, 1H), 8.32 (d, J=8.2 Hz, 1H),8.24-8.16 (m, 3H), 7.91 (dd, J=8.3, 1.2 Hz, 1H), 7.78 (dd, J=8.3, 1.6Hz, 1H), 7.41 (t, J=2.0 Hz, 1H), 7.15-7.11 (m, 2H). MS (EI): m/z 542(M−H).

Example 2872,4-Dichloro-N-[3-chloro-5-(5-cyano-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(287)

¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H), 8.22 (d, J=8.3 Hz, 1H), 8.19(d, J=1.5 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.79(dd, J=8.3, 1.6 Hz, 1H), 7.59 (dd, J=8.6, 2.1 Hz, 1H), 7.39 (t, J=1.9Hz, 1H), 7.12-7.08 (m, 2H). MS (EI): m/z 508 (M−H).

Example 2882,4-Dichloro-N-[3-chloro-5-(5-cyano-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(288)

¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 8.21 (d, J=8.3 Hz, 1H), 8.14(d, J=1.5 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.79 (dd, J=8.3, 1.5 Hz,1H), 7.36 (t, J=1.9 Hz, 1H), 7.11-7.06 (m, 2H), 2.16 (s, 3H). MS (EI):m/z 522 (M−H).

Example 289

2-Chloro-N-{3-chloro-5-[5-(1H-tetrazol-5-yl)-benzothiazol-2-yloxy]-phenyl}4-trifluoromethyl-benzenesulfonamide(289)

To a solution of2-Chloro-N-[3-chloro-5-(5-cyano-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(Example 286, 55 mg, 0.1 mmol) in 5 mL of toluene was addedazidotrimethylsilane (Aldrich, 26 uL, 0.2 mmol) and dibutyltin oxide(Aldrich, 3 mg, 0.01 mmol). The mixture was heated at 90° C. overnighttill there was no starting material remained by TLC. Cooled to roomtemperature, 1N HCl and EtOAc was added. The mixture was extracted 3×with EtOAc (30 mL). The organic layers were washed twice with a brinesolution (300 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by chromatography, eluted with 10% EtOAc/CH₂Cl₂ then 10%MeOH/CH₂Cl₂ to give 50 mg (85%) of product. ¹H NMR (400 MHz, DMSO-d₆) δ8.33 (d, J=8.2 Hz, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H),8.19 (s, 1H), 8.03 (dd, J=8.4, 1.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.44(t, J=2.0 Hz, 1H), 7.18 (t, J=2.0 Hz, 1H), 7.12 (t, J=1.9 Hz, 1H). MS(EI): m/z 585 (M−H).

Example 2902-Chloro-N-[3-chloro-5-(4-chloro-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(290)

¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (s, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.18(d, J=1.2 Hz, 1H), 7.93 (dd, J=8.1, 1.0 Hz, 1H), 7.90 (dd, J=8.3, 2.1Hz, 1H), 7.56 (dd, J=7.9, 1.0 Hz, 1H), 7.44 (t, J=2.0 Hz, 1H), 7.36 (t,J=8.0 Hz, 1H), 7.17 (t, J=2.0 Hz, 1H), 7.13 (t, J=1.9 Hz, 1H). MS (EI):m/z 551 (M−H).

Example 2912,4-Dichloro-N-[3-chloro-5-(4-chloro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(291)

¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.95(dd, J=8.0, 1.0 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.58 (dd, J=8.5, 2.0Hz, 1H), 7.56 (dd, J=8.0, 1.0 Hz, 1H), 7.41 (t, J=2.0 Hz, 1H), 7.37 (t,J=8.0 Hz, 1H), 7.13 (t, J=2.0 Hz, 1H), 7.10 (t, J=1.9 Hz, 1H). MS (EI):m/z 517 (M−H).

Example 2922,4-Dichloro-N-[3-chloro-5-(4-chloro-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(292)

¹H NMR (400 MHz, DMSO-d₆) δ 11.36 (s, 1H), 8.12 (s, 1H), 7.93 (dd,J=8.0, 1.0 Hz, 1H), 7.84 (s, 1H), 7.56 (dd, J=8.0, 1.0 Hz, 1H), 7.38 (t,J=2.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.14 (t, J=2.0 Hz, 1H), 7.11 (t,J=1.9 Hz, 1H), 2.19 (s, 3H). MS (EI): m/z 531 (M−H).

Example 2932-Chloro-N-[3-chloro-5-(4-methyl-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(293)

¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.18(d, J=1.0 Hz, 1H), 7.89 (dd, J=8.3, 1.2 Hz, 1H), 7.74 (dd, J=7.0, 2.3Hz, 1H), 7.37 (t, J=2.0 Hz, 1H), 7.30-7.24 (m, 2H), 7.21 (t, J=2.0 Hz,1H), 7.11 (t, J=1.9 Hz, 1H), 2.44 (s, 3H). MS (EI): m/z 531 (M−H).

Example 2942,4-Dichloro-N-[3-chloro-5-(4-methyl-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(294)

¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.92(d, J=2.0 Hz, 1H), 7.76 (dd, J=7.0, 2.2 Hz, 1H), 7.57 (dd, J=8.6, 2.0Hz, 1H), 7.35 (t, J=2.0 Hz, 1H), 7.31-7.24 (m, 2H), 7.16 (t, J=2.0 Hz,1H), 7.08 (t, J=1.9 Hz, 1H), 2.46 (s, 3H). MS (EI): m/z 497 (M−H).

Example 2952,4-Dichloro-N-[3-chloro-5-(4-methyl-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(295)

¹H NMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 8.08 (s, 1H), 7.84 (s, 1H),7.74 (dd, J=7.1, 2.1 Hz, 1H), 7.32 (t, J=2.0 Hz, 1H), 7.30-7.24 (m, 2H),7.16 (t, J=2.0 Hz, 1H), 7.09 (t, J=1.9 Hz, 1H), 2.44 (s, 3H), 2.17 (s,3H). MS (EI): m/z 511 (M−H).

Example 2962-Chloro-N-[3-chloro-5-(4-methoxy-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(296)

¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.18(s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.35-7.30 (m,2H), 7.11 (t, J=2.0 Hz, 1H), 7.08 (t, J=1.8 Hz, 1H), 7.04 (d, J=8.0 Hz,1H), 3.86 (s, 3H). MS (EI): m/z 547 (M−H).

Example 2972,4-Dichloro-N-[3-chloro-5-(4-methoxy-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(297)

¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H), 8.11 (d, J=8.6 Hz, 1H), 7.92(d, J=2.0 Hz, 1H), 7.57 (dd, J=8.6, 2.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H),7.33 (t, J=8.0 Hz, 1H), 7.31 (t, J=2.0 Hz, 1H), 7.08 (t, J=1.9 Hz, 1H),7.08-7.03 (m, 2H), 3.87 (s, 3H). MS (EI): m/z 513 (M−H).

Example 2982,4-Dichloro-N-[3-chloro-5-(4-methoxy-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(298)

¹H NMR (400 MHz, DMSOx-d6) δ 11.33 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H),7.50 (dd, J=8.0 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.30 (t, J=2.0 Hz, 1H),7.10 (t, J=2.0 Hz, 1H), 7.07 (t, J=1.8 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H),3.86 (s, 3H), 2.21 (s, 3H). MS (EI): m/z 527 (M−H).

Example 2992-Chloro-N-[3-chloro-5-(6-methyl-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(299)

¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.19(d, J=1.2 Hz, 1H), 7.90 (dd, J=8.4, 1.4 Hz, 1H), 7.74 (br s, 1H), 7.56(d, J=8.2 Hz, 1H), 7.34 (t, J=2.0 Hz, 1H), 7.27 (dd, J=8.3, 1.5 Hz, 1H),7.11 (t, J=2.0 Hz, 1H), 7.09 (t, J=1.9 Hz, 1H), 2.40 (s, 3H). MS (EI):m/z 531 (M−H).

Example 3002,4-Dichloro-N-[3-chloro-5-(6-methyl-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(300)

¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 8.08 (d, δ 8.6 Hz, 1H), 7.93(d, J=2.0 Hz, 1H), 7.76 (br s, 1H), 7.58 (dd, J=8.6, 2.1 Hz, 1H), 7.57(d, J=8.3 Hz, 1H), 7.32 (t, J=1.9 Hz, 1H), 7.28 (dd, J=8.3, 1.5 Hz, 1H),7.09-7.05 (m, 2H), 2.40 (s, 3H). MS (EI): m/z 497 (M−H).

Example 3012,4-Dichloro-N-[3-chloro-5-(6-methyl-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(301)

¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 8.09 (s, 1H), 7.86 (s, 1H),7.74 (br s, Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.31 (t, J=2.0 Hz, 1H),7.26 (dd, J=8.4, 1.3 Hz, 1H), 7.09-7.05 (m, 2H), 2.40 (s, 3H), 2.20 (s,3H). MS (EI): m/z 511 (M−H).

Example 3022-Chloro-N-[3-chloro-5-(6-chloro-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(302)

¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.18(d, J=1.1 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 7.91 (dd, J=8.3, 1.2 Hz, 1H),7.68 (d, J=8.6 Hz, 1H), 7.48 (dd, J=8.6, 2.2 Hz, 1H), 7.38 (t, J=1.9 Hz,1H), 7.13 (t, J=2.0 Hz, 1H), 7.10 (t, J=1.9 Hz, 1H). MS (EI): m/z 551(M−H).

Example 3032,4-Dichloro-N-[3-chloro-5-(6-chloro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(303)

¹H NMR (400 MHz, DMSO-d₆) δ 11.39 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.10(d, J=8.6 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.60(dd, J=8.5, 2.0 Hz, 1H), 7.49 (dd, J=8.6, 2.2 Hz, 1H), 7.36 (t, J=1.6Hz, 1H), 7.10-7.06 (m, 2H). MS (EI): m/z 517 (M−H).

Example 304

2-Chloro-N-[3-chloro-5-(6-fluoro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(304). ¹H NMR (400 MHz, DMSO-d₆) δ 11.54 (s, 1H), 8.31 (d, J=8.3 Hz,1H), 8.19 (br s, 1H), 7.93-7.88 (m, 2H), 7.70 (dd, J=8.9, 4.9 Hz, 1H),7.37 (br s, 1H), 7.31 (td, J=9.1, 2.7 Hz, 1H), 7.11 (t, J=2.0 Hz, 1H),7.09 (t, J=1.9 Hz, 1H). MS (EI): m/z 535 (M−H).

Example 305

2,4-Dichloro-N-[3-chloro-5-(6-fluoro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(305). ¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H), 8.09 (d, J=8.6 Hz,1H), 7.93 (d, J=1.9 Hz, 1H), 7.91 (dd, J=8.8, 2.7 Hz, 1H), 7.71 (dd,J=8.9, 4.9 Hz, 1H), 7.59 (dd, J=8.6, 2.1 Hz, 1H), 7.35 (t, J=2.0 Hz,1H), 7.32 (td, J=9.2, 2.7 Hz, 1H), 7.10-7.06 (m, 2H). MS (EI): m/z 501(M−H).

Example 306

2,4-Dichloro-N-[3-chloro-5-(6-fluoro-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(306). ¹H NMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 8.10 (s, 1H), 7.90(dd, J=8.7, 2.7 Hz, 1H), 7.86 (s, 1H), 7.68 (dd, J=8.9, 4.9 Hz, 1H),7.35-7.29 (m, 2H), 7.09-7.07 (m, 2H), 2.21 (s, 3H). MS (EI): m/z 515(M−H).

Example 307

2-Chloro-N-[3-chloro-5-(6-methoxy-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(307). ¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (s, 1H), 8.29 (d, J=8.2 Hz,1H), 8.18 (br s, 1H), 7.90 (dd, J=8.4, 1.3 Hz, 1H), 7.58 (d, J=8.9 Hz,1H), 7.57 (d, J=2.7 Hz, 1H), 7.33 (t, J=1.9 Hz, 1H), 7.10 (t, J=2.0 Hz,1H), 7.08 (t, J=1.9 Hz, 1H), 7.04 (dd, J=8.9, 2.7 Hz, 1H), 3.80 (s, 3H).MS (EI): m/z 547 (M−H).

Example 308

2,4-Dichloro-N-[3-chloro-5-(6-methoxy-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(308). ¹H NMR (400 MHz, DMSO-d₆) δ 11.36 (s, 1H), 8.08 (d, δ 8.6 Hz,1H), 7.93 (d, J=2.0 Hz, 1H), 7.62-7.57 (m, 3H), 7.30 (t, J=2.0 Hz, 1H),7.07-7.03 (m, 3H), 3.80 (s, 3H). MS (EI): m/z 513 (M−H).

Example 309

2,4-Dichloro-N-[3-chloro-5-(6-methoxy-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(309). ¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 8.09 (s, 1H), 7.86 (s,1H), 7.58-7.55 (m, 2H), 7.29 (t, J=2.0 Hz, 1H), 7.08-7.03 (m, 3H), 3.80(s, 3H), 2.21 (s, 3H). MS (EI): m/z 529 (M+H).

Example 310

2-[3-Chloro-5-(2-chloro-4-trifluoromethyl-benzenesulfonylamino)-phenoxy]-benzothiazole-6-carboxylicacid ethyl ester (310). ¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (s, 1H), 8.63(d, J=1.5 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.18 (s, 1H), 8.00 (dd,J=8.5, 1.7 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.40(t, J=1.9 Hz, 1H), 7.16 (t, J=1.9 Hz, 1H), 7.12 (t, J=1.8 Hz, 1H), 4.33(q, J=7.1 Hz, 1H), 1.34 (t, J=7.1 Hz, 1H). MS (EI): m/z 589 (M−H).

Example 311

2-[3-Chloro-5-(2-chloro-4-trifluoromethyl-benzenesulfonylamino)-phenoxy]-benzothiazole-6-carboxylicacid ethyl ester (311). ¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 8.65(d, J=1.2 Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 8.01 (dd, J=8.5, 1.5 Hz, 1H),7.93 (d, J=2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, —1H), 7.59 (dd, J=8.5, 2.0Hz, 1H), 7.39 (br s, 1H), 7.12 (br s, 1H), 7.10 (br s, 1H), 4.34 (q,J=7.1 Hz, 1H), 1.34 (t, J=7.1 Hz, 1H). MS (EI): m/z 555 (M−H).

Example 312

3,5-Dinitro-benzoic acid methyl ester (312). To 3,5-Dinitro-benzoic acid(Aldrich, 21.2 g, 100 mmol) was added SOCl₂. The mixture was refluxedovernight. The excess SOCl₂ was removed under reduced pressure. Theresidue was dissolved in 100 mL of MeOH, cooled in ice bath, andtriethylamine (Aldrich, 21 mL, 150 mmol) was added slowly added. Afterthe mixture was stirred at ambient temperature for 3 h, solvent wasremoved under reduced pressure. The residue was diluted with EtOAc and1N HCl. The mixture was extracted 3× with EtOAc (100 mL). The organiclayers were washed twice with a brine solution (100 μL), dried overNa₂SO₄. Removal of the solvent gave 22.0 g (97%) of product, which waspure enough for the next reaction. ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (t,J=2.1 Hz, 1H), 8.92 (d, J=2.1 Hz, 2H), 3.99 (s, 3H).

Example 313

3-Amino-5-nitro-benzoic acid methyl ester (313). 3,5-Dinitro-benzoicacid methyl ester (Example 312, 13.7 g, 60.6 mmol), Pd/C (Aldrich, 1.34g, 10%, 0.61 mmol), triethylamine (Aldrich, 36.4 mL, 273 mmol) wasdissolved in 30 mL of CH₃CN. To the above solution was added a solutionof HCOOH (Aldrich, 9.7 mL, 261 mmol) in 30 mL of CH₃CN dropwise. Themixture was then refluxed for 2 h. After cooled to room temperature, themixture was filtered through a Celite pad, washed with EtOAc, and thefiltrate was concentrated. The residue was purified by chromatography(5%-10% EtOAc/CH₂Cl₂) to give 7.0 g (59%) of product. ¹H NMR (400 MHz,DMSO-d₆) δ 7.74 (t, J=2.0 Hz, 1H), 7.59 (t, J=2.2 Hz, 1H), 7.55 (t,J=2.0 Hz, 1H), 6.16 (s, 2H), 3.87 (s, 3H).

Example 314

3-Hydroxy-5-nitro-benzoic acid (314). To a solution of3-amino-5-nitro-benzoic acid methyl ester (Example 313, 1.96 g, 10 mmol)in 23 mL of H₂O and 5 mL of con. H₂SO₄ at 0° C., was added a solution ofNaNO₂ (Aldrich, 900 mg, 13 mmol) in 9 mL of H₂O. After 50 min stirring,the resulting diazonium salt was added to a solution of 17 mL of H₂O and17 mL of con. H₂SO₄ at 90° C. After stirred at 90° C. for 90 min, themixture was cooled to room temperature and brought to pH 3 with con.NH₄OH. The mixture was extracted 3× with EtOAc (100 mL). The organiclayers were washed twice with a brine solution (100 mL), dried overNa₂SO₄ and concentrated. The residue was purified by chromatography(5%-10% MeOH/CH₂Cl₂) to give 705 mg (39%) of product. ¹H NMR (400 MHz,DMSO-d₆) δ 13.64 (br s, 1H), 10.84 (s, 1H), 8.08 (t, J=1.8 Hz, 1H), 7.75(t, J=2.2 Hz, 1H), 7.70 (dd, J=2.2, 1.3 Hz, 1H), 6.16 (s, 2H), 3.87 (s,3H). MS (EI): m/z 184 (M+H).

Example 315

3-(5-Chloro-benzothiazol-2-yloxy)-N-ethyl-5-nitro-benzamide (315). To asolution of 3-hydroxy-5-nitro-benzoic acid (Example 314, 705 mg, 3.85mmol) in DMF was added NaH (Aldrich, 340 mg, 60%, 8.5 mmol). The mixturewas stirred for 10 min, then 2,5-dichlorobenzothiazole (Example 253, 782mg, 3.85 mmol) was added. The mixture was heated at 60° C. till there isno starting material remained by TLC. After cooled to room temperature,the mixture was poured to ice/1N HCl, and filtered. The precipitate wastriturated with CH₂Cl₂/hexanes to give 990 mg (74%) of product. ¹H NMR(400 MHz, DMSO-d₆) δ 8.67 (t, J=1.8 Hz, 1H), 8.57 (t, J=2.0 Hz, 1H),8.41 (dd, J=2.2, 1.4 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.82 (d, J=2.1 Hz,1H), 7.44 (dd, J=8.6, 2.1 Hz, 1H). MS (EI): m/z 351 (M+H). To a solutionof the above product in THF was added HOAT (385 mg, 2.83 mmol), HBTU(1.07 g, 2.83 mmol), N-methylmorpholine (Aldrich, 0.8 mL, 7.1 mmol)followed by ethylamine (Aldrich, 1.7 mL, 2M solution in THF, 3.4 mmol).The mixture was stirred overnight. THF was removed under reducedpressure and the residue was diluted with EtOAc and 1N HCl. The mixturewas extracted 3× with EtOAc (500 mL). The organic layers were washedtwice with a brine solution (50 mL), dried over Na₂SO₄ and concentrated.The residue was purified by chromatography (15% EtOAc/CH₂Cl₂) to give625 mg (56%) of product. ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (br t, J=5.3Hz, 1H), 8.68 (t, J=1.8 Hz, 1H), 8.59 (t, J=2.0 Hz, 1H), 8.38 (t, J=1.9Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.44 (dd,J=8.6, 2.1 Hz, 1H), 3.33 (m, 2H), 1.15 (t, J=7.2 Hz, 1H). MS (EI): m/z378 (M+H).

Example 316

3-Amino-5-(5-chloro-benzothiazol-2-yloxy)-N-ethyl-benzamide (316).3-Amino-5-(5-chloro-benzothiazol-2-yloxy)-N-ethyl-benzamide (316) wassynthesized from3-(5-chloro-benzothiazol-2-yloxy)-N-ethyl-5-nitro-benzamide (315, 620mg, 1.64 mmol) in a similar manner as described in Examples 16-23(Method A). ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (br t, J=5.5 Hz, 1H), 7.98(d, J=8.6 Hz, 1H), 7.82 (d, J=2.1 Hz, 1H), 7.39 (dd, J=8.6, 2.1 Hz, 1H),7.05 (t, J=1.8 Hz, 1H), 6.95 (t, J=1.8 Hz, 1H), 6.66 (t, J=1.9 Hz, 1H),3.23 (m, 2H), 1.08 (t, J=7.2 Hz, 1H). MS (EI): m/z 378 (M+H).

Example 317

3-(5-Chloro-benzothiazol-2-yloxy)-5-(2-chloro-4-trifluoromethylbenzenesulfonylamino)-N-ethyl-benzamide(317).3-(5-Chloro-benzothiazol-2-yloxy)-5-(2-chloro-4-trifluoromethylbenzenesulfonylamino)-N-ethyl-benzamide(317) was synthesized (71%) from3-amino-5-(5-chloro-benzothiazol-2-yloxy)-N-ethyl-benzamide (316) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.41 (s, 1H), 8.51 (br t, J=5.4 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.17(s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.76 (d, J=2.1Hz, 1H), 7.60 (m, 2H), 7.42 (dd, J=8.6, 2.1 Hz, 1H), 7.29 (t, J=1.9 Hz,1H), 3.23 (m, 2H), 1.07 (t, J=7.2 Hz, 1H). MS (EI): m/z 590 (M+H).

Example 318

3-(5-Chloro-benzothiazol-2-yloxy)-5-(2,4-dichlorobenzenesulfonylamino)-N-ethyl-benzamide(318).3-(5-Chloro-benzothiazol-2-yloxy)-5-(2,4-dichloro-benzenesulfonylamino)-N-ethyl-benzamide(318) was synthesized (83%) from3-amino-5-(5-chloro-benzothiazol-2-yloxy)-N-ethyl-benzamide (316) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.26 (s, 1H), 8.51 (br t, J=5.5 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.01(d, J=8.6 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H),7.60-7.56 (m, 3H), 7.43 (dd, J=8.6, 2.1 Hz, 1H), 7.25 (t, J=2.1 Hz, 1H),3.23 (m, 2H), 1.07 (t, J=7.2 Hz, 1H). MS (EI): m/z 554 (M−H).

Example 319

3-(5-Chloro-benzothiazol-2-yloxy)-5-(2,4-dichloro-5-methyl-benzenesulfonylamino)-N-ethyl-benzamide(319).3-(5-Chloro-benzothiazol-2-yloxy)-5-(2,4-dichloro-5-methyl-benzenesulfonylamino)-N-ethyl-benzamide(319) was synthesized (81%) from3-amino-5-(5-chloro-benzothiazol-2-yloxy)-N-ethyl-benzamide (316) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.24 (s, 1H), 8.50 (br t, J=5.3 Hz, 1H), 8.08 (s, 1H), 7.99 (d, J=8.6Hz, 1H), 7.85 (s, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.58-7.55 (m, 2H), 7.43(dd, J=8.6, 2.1 Hz, 1H), 7.26 (t, J=2.1 Hz, 1H), 3.23 (m, 2H), 2.19 (s,3H), 1.07 (t, J=7.2 Hz, 1H). MS (EI): m/z 570 (M+H).

Example 320

[3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenyl]-carbamic acidtert-butyl ester (320).[3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenyl]-carbamic acidtert-butyl ester (320) was synthesized (57%) from 3,5-dihydroxy-benzoicacid (Aldrich, 770 mg, 5 mmol) and 2,5-dichlorobenzothiazole (253, 2.03g, 10 mmol) in a similar manner as described in Example 263. ¹H NMR (400MHz, DMSO-d₆) δ 9.91 (br s, 1H), 8.02 (d, J=8.6 Hz, 2H), 7.84 (d, J=2.1Hz, 2H), 7.54-7.51 (m, 2H), 7.42 (dd, J=8.6, 2.1 Hz, 2H), 7.34 (t, J=2.2Hz, 1H), 1.47 (s, 9H). MS (EI): m/z 560 (M+H).

Example 321

3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenylamine (321).3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenylamine (321) wassynthesized (94%) from[3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenyl]-carbamic acidtert-butyl ester (320) in a similar manner as described in Example 273.¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=8.6 Hz, 2H), 7.83 (d, J=2.0 Hz,2H), 7.40 (dd, J=8.6, 2.1 Hz, 2H), 6.70 (t, J=2.2 Hz, 1H), 6.58-6.55 (m,2H), 5.89 (s, 2H). MS (EI): m/z 460 (M+H).

Example 322

N-[3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(322).N-[3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(322) was synthesized (58%) from3,5-bis-(5-chloro-benzothiazol-2-yloxy)-phenylamine (321) in a similarmanner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.57(br s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J=8.6 Hz,2H), 7.87 (d, J=8.3 Hz, 1H), 7.78 (d, J=2.0 Hz, 2H), 7.45-7.41 (m, 3H),7.15-7.14 (m, 2H). MS (EI): m/z 700 (M−H).

Example 323

N-[3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenyl]-2,4-dichloro-benzenesulfonamide(323).N-[3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenyl]-2,4-dichloro-benzenesulfonamide(323) was synthesized (57%) from3,5-bis-(5-chlorobenzothiazol-2-yloxy)-phenylamine (321) in a similarmanner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.42(br s, 1H), 8.11 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.6 Hz, 2H), 7.95 (d,J=2.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 2H), 7.53 (d, J=8.6, 1.9 Hz, 1H),7.45-7.41 (m, 3H), 7.12-7.09 (m, 2H). MS (EI): m/z 666 (M−H).

Example 324

N-[3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenyl]-2,4-dichloro-5-methyl-benzenesulfonamide(324).N-[3,5-Bis-(5-chloro-benzothiazol-2-yloxy)-phenyl]-2,4-dichloro-5-methyl-benzenesulfonamide(324) was synthesized (70%) from3,5-bis-(5-chloro-benzothiazol-2-yloxy)-phenylamine (321) in a similarmanner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.40(br s, 1H), 8.11 (s, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.88 (s, 1H), 7.76 (d,J=2.0 Hz, 2H), 7.43 (dd, J=8.6, 1.9 Hz, 1H), 7.39 (t, J=1.8 Hz, 2H),7.12-7.09 (m, 2H), 2.09 (s, 3H). MS (EI): m/z 680 (M−H).

Example 325

3-Chloro-5-nitro-benzoic acid methyl ester (325).3-Chloro-5-nitro-benzoic acid methyl ester (325) was synthesized (85%)from 3-amino-5-nitro-benzoic acid methyl ester (313) in a similar manneras described in Example 255. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (t, J=2.1Hz, 1H), 8.53 (dd, J=2.1, 1.4 Hz, 1H), 8.33 (dd, J=1.8, 1.6 Hz, 1H),3.94 (s, 3H).

Example 326

3-Chloro-5-nitro-benzoic acid (326). To a solution of3-chloro-5-nitro-benzoic acid methyl ester (325, 2.75 g, 12.76 mmol) in60 mL of MeOH was added a solution of NaOH (EM, 5.10 g, 127.6 mmol) in35 mL of H₂O. The mixture was stirred for 2 h. MeOH was removed underreduced pressure, and the mixture was diluted with water, brought to pH2 with con. HCl. Filtration followed by washing with water gave 2.35 g(92%) desired product. ¹H NMR (400 MHz, DMSO-d₆) δ 14.02 (s, 1H),8.57-8.52 (m, 2H), 8.31 (dd, J=1.9, 1.2 Hz, 1H), 3.94 (s, 3H). MS (EI):m/z 200 (M−H).

Example 327

(3-Chloro-5-nitro-phenyl)-acetic acid methyl ester (327). To3-Chloro-5-nitro-benzoic acid (326, 2.35 g, 11.7 mmol) was added SOCl₂.The mixture was refluxed overnight. The excess SOCl₂ was removed underreduced pressure to give the corresponding acid chloride. The above acidchloride was dissolved in 15 mL of CH₃CN, cooled to 0° C. A mixture ofTMSCHN₂ (Aldrich, 11.7 mL, 2M, 23.4 mmol) and Et₃N, which was alsocooled to 0° C., was added. The resulting mixture was stirred for 4 h.The solvent was removed under reduced pressure and the residue wasdiluted with EtOAc and 1N HCl. The mixture was extracted 3× with EtOAc(100 mL). The organic layers were washed twice with a brine solution(100 mL), dried over Na₂SO₄ and concentrated. The residue was purifiedby chromatography (20% EtOAc/hexanes) to give 2.1 g (79%) of product. ¹HNMR (400 MHz, DMSO-d₆) δ 8.53-8.50 (m, 2H), 8.35 (t, J=1.7 Hz, 1H), 7.35(s, 1H).

To a solution of the above product (2.1 g, 9.29 mmol) in 45 mL of MeOHat −25° C. was added a mixture of AgOBz (Aldrich, 213 mg, 0.93 mmol) andEt₃N (Aldrich, 3.9 mL, 27.9 mmol) dropwise. The resulting mixture wasstirred till ambient temperature was reached. The solvent was removedunder reduced pressure and the residue was diluted with EtOAc and 1NHCl. The mixture was extracted 3× with EtOAc (50 mL). The organic layerswere washed twice with a brine solution (50 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by chromatography (20%EtOAc/hexanes) to give 925 mg (43%) of product. ¹H NMR (400 MHz, CDCl₃)δ 8.15 (t, J=2.0 Hz, 1H), 8.07 (t, J=1.5 Hz, 1H), 7.63 (t, J=1.5 Hz,1H), 3.74 (s, 2H), 3.73 (s, 3H).

Example 328

(3-Chloro-5-nitro-phenyl)-acetic acid (328). To a solution of(3-Chloro-5-nitro-phenyl)-acetic acid methyl ester (327, 920 mg, 4.0mmol) in 20 mL of MeOH was added a solution of NaOH (EM, 1.6 g, 40 mmol)in 10 mL of H₂O. The mixture was stirred for 2 h. MeOH was removed underreduced pressure, and the mixture was diluted with water, brought to pH2 with con. HCl. The mixture was extracted 3× with EtOAc (50 mL). Theorganic layers were washed twice with a brine solution (50 mL), driedover Na₂SO₄. Removal of the solvent gave 810 mg (94%) of product. ¹H NMR(400 MHz, DMSO-d₆) δ 8.17-8.14 (m, 2H), 7.84 (br s, 1H), 3.77 (s, 3H).

Example 329

5-Chloro-2-(3-chloro-5-nitro-benzyl)-benzothiazole (329).5-Chloro-2-(3-chloro-5-nitro-benzyl)-benzothiazole (329) was synthesized(92%) from (3-chloro-5-nitro-phenyl)-acetic acid (328, 430 mg, 2.0 mmol)and 2-amino-4-chloro-benzothiazole hydrochloride (6, 392 mg, 2.0 mmol)in a similar manner as described in Example 8. ¹H NMR (400 MHz, DMSO-d₆)δ 8.30 (br s, 1H), 8.22 (t, J=2.0 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.06(d, J=2.0 Hz, 1H), 8.03 (br s, 1H), 7.47 (dd, J=8.6, 2.0 Hz, 1H), 4.72(s, 2H). MS (EI): m/z 339 (M+H).

Example 330

3-Chloro-5-(5-chloro-benzothiazol-2-ylmethyl)-phenylamine (330).3-Chloro-5-(5-chloro-benzothiazol-2-ylmethyl)-phenylamine (330) wassynthesized (95%) from5-chloro-2-(3-chloro-5-nitro-benzyl)-benzothiazole (329) in a similarmanner as described in Examples 16-23 (Method A). ¹H NMR (400 MHz,DMSO-d₆) δ 8.07 (d, J=8.6 Hz, 1H), 8.046 (d, J=2.0 Hz, 1H), 7.46 (dd,J=8.6, 2.1 Hz, 1H), 6.53 (br s, 1H), 6.49 (t, J=1.9 Hz, 1H), 6.46 (br s,1H), 4.30 (s, 2H). MS (EI): m/z 309 (M+H).

Example 331

2-Chloro-N-[3-chloro-5-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]4-trifluoromethyl-benzenesulfonamide(331).2-Chloro-N-[3-chloro-5-(5-chlorobenzothiazol-2-ylmethyl)-phenyl]4-trifluoromethyl-benzenesulfonamide(331) was synthesized (83%) from3-Chloro-5-(5-chloro-benzothiazol-2-ylmethyl)-phenylamine (330) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.26 (br s, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.08-8.03 (m, 3H), 7.69 (dd,J=8.3, 1.3 Hz, 1H), 7.49 (dd, J=8.6, 2.1 Hz, 1H), 7.19 (t, J=1.4 Hz,1H), 7.09 (br s, 1H), 7.04 (t, J=1.9 Hz, 1H), 4.42 (s, 2H). MS (EI): m/z549 (M−H).

Example 332

2,4-Dichloro-N-[3-chloro-5-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide(332).2,4-Dichloro-N-[3-chloro-5-(5-chlorobenzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide(332) was synthesized (78%) from3-chloro-5-(5-chloro-benzothiazol-2-ylmethyl)-phenylamine (330) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.09 (br s, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.95(d, J=8.6 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.50 (dd, J=8.6, 2.0 Hz, 1H),7.34 (dd, J=8.6, 2.1 Hz, 1H), 7.17 (br s, 1H), 7.04-7.01 (m, 2H), 4.41(s, 2H). MS (EI): m/z 515 (M−H).

Example 333

2,4-Dichloro-N-[3-chloro-5-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]-5-methyl-benzenesulfonamide(333).2,4-Dichloro-N-[3-chloro-5-(5-chlorobenzothiazol-2-ylmethyl)-phenyl]-5-methyl-benzenesulfonamide(333) was synthesized (83%) from3-chloro-5-(5-chloro-benzothiazol-2-ylmethyl)-phenylamine (330) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.03 (br s, 1H), 8.05 (d, J=8.6 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.01(s, 1H), 7.76 (s, 1H), 7.48 (dd, J=8.6, 2.1 Hz, 1H), 7.17 (br s, 1H),7.07 (br s, 1H), 7.04 (d, J=1.9 Hz, 1H), 4.42 (s, 2H), 2.19 (s, 3H). MS(EI): m/z 529 (M−H).

Example 334

Library compounds. To a solution of3-chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenylamine (273, 31 mg, 0.1mmol) in 1 mL of pyridine was added the corresponding sulfonyl chloride.The mixture was stirred at 40° C. overnight. The pyridine was removedusing Genevac vacuum system. The residue was purified by chromatographyusing a silica cartage (Varian, 2 g) and Vacmaster system, eluted withsuitable solvent system (50%-80% CH₂Cl₂/hexanes or 5%-25%EtOAc/hexanes). The purity of the products was checked by HPLC and LCMS.

Ar

Product 40 mg 60 mg 50 mg 45 mg MS 479(M + H) 587(M + H) 499(M + H)483(M + H) Ar

Product 50 mg 55 mg 25 mg 35 mg MS 501(M + H) 602(M + H) 502(M + H)485(M + H) Ar

Product 46 mg 45 mg 50 mg 50 mg MS 613(M + H) 519(M + H) 519(M + H)457(M + H) Ar

Product 38 mg 44 mg 50 mg 40 mg MS 469(M + H) 510(M + H) 485(M + H)519(M + H) Ar

Product 40 mg 75 mg 50 mg 40 mg MS 501(M + H) 597(M + H) 499(M + H)470(M + H) Ar

Product 20 mg 45 mg 45 mg 38 mg MS 493(M + H) 487(M + H) 535(M + H)525(M + H) Ar

Product 40 mg 38 mg 70 mg 62 mg MS 535(M + H) 535(M + H) 666(M + H)605(M + H) Ar

Product 26 mg 50 mg 35 mg 65 mg MS 455(M + H) 542(M + H) 487(M + H)622(M + H) Ar

Product 38 mg 25 mg 45 mg 60 mg MS 474(M + H) 487(M + H) 521(M + H)581(M + H) Ar

Product 50 mg 30 mg 45 mg 50 mg MS 553(M + H) 496(M + H) 519(M + H)688(M + H) Ar

Product 35 mg 20 mg 25 mg 25 mg MS 465(M + H) 559(M + H) 700(M + H)567(M + H) Ar

Product 25 mg 45 mg 45 mg 60 mg MS 567(M + H) 555(M + H) 523(M + H)510(M + H) Ar

Product 12 mg 45 mg 45 mg 18 mg MS 496(M + H) 503(M + H) 624(M + H)509(M + H) Ar

Product 50 mg 20 mg 20 mg 50 mg MS 496(M + H) 564(M + H) 527(M + H)545(M + H) Ar

Product 40 mg 10 mg 20 mg 40 mg MS 509(M + H) 476(M + H) 502(M + H)481(M + H) Ar

Product 45 mg 25 mg 15 mg 40 mg MS 515(M + H) 515(M + H) 524(M + H)469(M + H)

Example 402

(2-Chloro-5-methanesulfonyl-phenyl)-carbamic acid tert-butyl ester(402). (2-Chloro-5-methanesulfonyl-phenyl)-carbamic acid tert-butylester was synthesized (79%) from 2-chloro-5-methanesulfonyl-benzoic acid(401) in a similar manner as described in Example 263. ¹H NMR (400 MHz,DMSO-d₆) δ 9.02 (S, 1H), 8.21 (d, J=2.1 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H),7.65 (dd, J=8.4, 2.2 Hz, 1H), 3.23 (s, 3H), 1.48 (s, 9H). MS (EI): m/z304 (M−H).

Example 403

2-Chloro-5-methanesulfonyl-phenylamine (403).2-Chloro-5-methanesulfonyl-phenylamine was synthesized from(2-chloro-5-methanesulfonyl-phenyl)-carbamic acid tert-butyl ester (402)in a similar manner as described in Example 273. This product withoutfurther purification was used directly in Example 404. NMR (400 MHz,DMSO-d₆) δ 7.45 (d, J=8.3 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.01 (dd,J=8.3, 2.2 Hz, 1H), 5.94 (s, 2H), 3.14 (s, 3H).

Example 404

5-Methanesulfonyl-benzothiazole-2-thiol (404).5-Methanesulfonyl-benzothiazole-2-thiol was synthesized from2-chloro-5-methanesulfonyl-phenylamine (403) in a similar manner asdescribed in Example 252. This product without further purification wasused directly in Example 410. ¹H NMR (400 MHz, DMSO-d₆) δ 14.25 (br s,1H), 7.98 (d, J=8.4 Hz, 1H), 7.81 (dd, J=8.4, 1.8 Hz, 1H), 7.72 (d,J=1.7 Hz, 1H), 3.26 (s, 3H).

Example 405

6-Trifluoromethoxy-benzothiazol-2-ylamine (405). To a solution of4-trifluoromethoxyaniline (Aldrich, 4.83 g, 30 mmol) in 50 mL of AcOH,was added KSCN (Aldrich, 11.64 g, 120 mmol). After the mixture wasstirred for 30 min, a solution of bromine (Aldrich, 1.55 mL, 30 mmol) in20 mL of AcOH was added over 30 min period, and the resulting reactionmixture was stirred overnight. The mixture was diluted with ice/water,brought to pH 8 with conc. NH₄OH. The mixture extracted 3× with EtOAc(300 mL). The organic layers were washed twice with a brine solution(300 mL), dried over Na₂SO₄ and concentrated. The residue was purifiedby chromatography (40%-45% EtOAc/Hexanes) to give 6.0 g (85%) ofproduct. ¹H NMR (400 MHz, DMSO-d₆) δ 7.76 (d, J=2.2 Hz, 1H), 7.63 (s,2H), 7.36 (d, J=8.7 Hz, 1H), 7.17 (dd, J=8.7, 2.4 Hz, 1H), 3.23 (s, 3H).MS (EI): m/z 235 (M+H).

Example 406

1-(2-Amino-benzothiazol-6-yl)-ethanone (406).1-(2-Amino-benzothiazol-6-yl)-ethanone was synthesized from4′-aminoacetophenone (Aldrich) in a similar manner as described inExample 405 except the workup. After the mixture was brought to pH 8,precipitate was formed. Filtration followed by washing with water gave ayellow solid, which was triturated with CH₂Cl₂/heaxanes. This productwithout further purification was used directly in Example 415. ¹H NMR(400 MHz, DMSO-d₆) δ 8.32 (d, J=1.7 Hz, 1H), 7.91 (s, 2H), 7.83 (dd,J=8.4, 1.7 Hz, 1H), 7.37 (dd, J=8.4 Hz, 1H), 2.57 (s, 3H). MS (EI): m/z193 (M+H).

Example 407

6-Trifluoromethyl-benzothiazol-2-ylamine (407).6-Trifluoromethyl-benzothiazol-2-ylamine was synthesized from4-trifluoromethylaniline (Aldrich) in a similar manner as described inExample 405. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.16 (d, J=8.2HZ, 1H), 7.99 (d, J=8.1 Hz, 1H).

Example 408

2-Amino-benzothiazole-6-carbonitrile (408).2-Amino-benzothiazole-6-carbonitrile was synthesized from4-amino-benzonitrile (Aldrich) in a similar manner as described inExample 406. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=1.7 Hz, 1H), 8.08(s, 2H), 7.62 (dd, J=8.4, 1.7 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H). MS (EI):m/z 176 (M+H).

TABLE 17

Compound X Method 409 5-NO₂ A 410 5-SO₂Me A 411 6-NO₂ B 412 6-SO₂Me B413 6-OCF₃ B 414 6-CF₃ B 415 6-COMe B 416 6-CN B

The compounds of Table 17 were prepared using the method A as describedin Example 253 or method B as described in Example 255.

Example 409

2-Chloro-5-nitro-benzothiazole (409). ¹H NMR (400 MHz, DMSO-d₆) δ 8.79(d, J=2.2 Hz, 1H), 8.42 (d, J=8.9 Hz, 1H), 8.36 (dd, J=8.9, 2.2 Hz, 1H).

Example 410

2-Chloro-5-methanesulfonyl-benzothiazole (410). ¹H NMR (400 MHz,DMSO-d₆) δ 8.47 (d, J=1.6 Hz, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.03 (dd,J=8.5, 1.8 Hz, 1H), 3.31 (s, 3H).

Example 411

2-Chloro-6-nitro-benzothiazole (411). ¹H NMR (400 MHz, DMSO-d₆) 9.18 (d,J=2.4 Hz, 1H), 8.37 (dd, J=9.0, 2.5 Hz, 1H), 8.17 (d, J=9.0 Hz, 1H).

Example 412

2-Chloro-6-methanesulfonyl-benzothiazole (412). ¹H NMR (400 MHz,DMSO-d₆) δ 8.82 (d, J=1.8 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.08 (dd,J=8.5, 1.8 Hz, 1H), 3.28 (s, 3H).

Example 413

2-Chloro-6-trifluoromethoxy-benzothiazole (413). ¹H NMR (400 MHz,DMSO-d₆) δ 8.28 (d, J=1.5 Hz, 1H), 8.08 (d, J=8.9 HZ, 1H), 7.57 (dd,J=8.9, 1.5 Hz, 1H).

Example 414

2-Chloro-6-trifluoromethylbenzothiazole (414). ¹H NMR (400 MHz, DMSO-d₆)δ 8.64 (s, 1H), 8.16 (d, J=8.4 HZ, 1H), 7.87 (dd, J=8.4, 1.6 Hz, 1H).

Example 415

1-(2-Chloro-benzothiazol-6-yl)-ethanone (415). ¹H NMR (400 MHz, DMSO-d₆)δ 8.81 (d, J=1.6 Hz, 1H), 8.11 (dd, J=8.6, 1.7 HZ, 1H), 8.07 (d, J=8.6Hz, 1H), 2.66 (s, 3H).

Example 416

2-Chloro-6-cyanobenzothiazole (416). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70(s, 1H), 8.16 (d, J=8.2 HZ, 1H), 7.99 (d, J=8.1 Hz, 1H).

Example 417

3,5-Dichloro-4-(4-chloro-benzothiazol-2-yloxy)-phenylamine (417). Tosolution of 2,4-dichlorobenzothiazole (255, 2.23 g, 11 mmol) and4-amino-2,6-dichlorophenol (Aldrich, 1.78 g, 10 mmol) in 10 mL of DMSOwas add K₂CO₃ (Aldrich, 4.14 g, 30 mmol). The mixture was heated at 145°C. for 4 h. After cooled to room temperature, the reaction mixture wasdiluted with EtOAc (300 mL) and filtered through a pad of silica gel andactivated carbon followed by washing with EtOAc (500 mL). The filtratewas concentrated and the residue was purified by chromatography (20%-30%EtOAc/Hexanes) to give 1.15 g (33%) of product. ¹H NMR (400 MHz,DMSO-d₆) δ 7.92 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.34 (t,J=8.0 Hz, 1H), 6.75 (s, 2H), 5.93 (s, 2H). MS (EI): m/z 345 (M+H).

Example 418

3,5-Dichloro-4-(4-methoxy-benzothiazol-2-yloxy)-phenylamine (418).3,5-Dichloro-4-(4-methoxy-benzothiazol-2-yloxy)-phenylamine wassynthesized (21%) from 2-chloro-4-methoxybenzotiazole (257) and4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described inExample 417. ¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (d, J=8.0 Hz, 1H), 7.28(t, J=8.1 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.73 (s, 2H), 5.86 (s, 2H),3.85 (s, 3H). MS (EI): m/z 341 (M+H).

Example 419

3,5-Dichloro-4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylamine(419).3,5-Dichloro-4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylamine wassynthesized (76%) from 2-chloro-6-trifluoromethoxybenzotiazole (413) and4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described inExample 417. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J=1.6 Hz, 1H), 7.80(d, J=8.8 Hz, 1H), 7.44 (ddd, J=8.8, 1.6, 0.8 Hz, 1H), 6.74 (s, 2H),5.87 (s, 2H). MS (EI): m/z 395 (M+H).

Example 420

3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420).3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine wassynthesized (65%) from 2,6-dichlorobenzotiazole (259) and4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described inExample 417. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 7.78(d, J=8.7 Hz, 1H), 7.47 (dd, J=8.7, 2.2 Hz, 1H), 6.73 (s, 2H), 5.88 (s,2H). MS (EI): m/z 345 (M+H).

Example 421

2-Chloro-N-(3,5-dichloro-4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide(421). To a solution of 4-amino-2,6-dichlorophenol (Aldrich, 5.9 g, 33mmol) in 30 mL of THF was added2-chloro-4-trifluoromethylbenzenesulfonyl chloride (4.19 g, 15 mmol).The mixture was stirred overnight. The reaction mixture was filtered andwashed with EtOAc. The filtrate was washed with 2N HCl, twice with abrine solution, dried over Na₂SO₄ and concentrated. The residue waspurified by chromatography (20%-25% EtOAc/hexanes) to give 5.7 g (90%)of product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 10.15 (s, 1H),8.19 (d, J=8.3 Hz, 1H), 8.16 (d, J=1.1 Hz, 1H), 7.92 (dd, J=8.3, 2.2 Hz,1H), 7.06 (s, 2H). MS (EI): m/z 418 (M+H).

Example 422

2-Chloro-N-(3-chloro-4-hydroxy-phenyl)₄-trifluoromethyl-benzenesulfonamide(422).2-Chloro-N-(3-chloro-4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamidewas synthesized (92%) from 4-amino-2-chlorophenol (Aldrich) and2-chloro-4-trifluoromethylbenzenesulfonyl chloride in a similar manneras described in Example 421. ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H),10.17 (s, 1H), 8.14 (d, J 1.0 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.88 (dd,J=8.5, 1.4 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.88 (dd, J=8.7, 2.5 Hz,1H), 6.82 (d, J=8.7 Hz, 1H). MS (EI): m/z 384 (M+H).

Example 423

2-Chloro-N-(4-hydroxy-phenyl)₄-trifluoromethyl-benzenesulfonamide (423).2-Chloro-N-(4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide wassynthesized (98%) from 4-aminophenol (Aldrich) and2-chloro-4-trifluoromethylbenzenesulfonyl chloride in a similar manneras described in Example 421. ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H),9.39 (s, 1H), 8.12 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.1 Hz,1H), 6.89 (m, 2H), 6.61 (m, 2H). MS (EI): m/z 384 (M+H).

Examples 424-432

The compounds of Table 18 were prepared using Method D described inExamples 70-91 and the corresponding arylsulfonyl chloride.

TABLE 18

Compound X A B 424 4-Cl CF₃ H 425 4-Cl Cl H 426 4-Cl Cl Me 427 4-OMe CF₃H 428 4-OMe Cl H 429 4-OMe Cl Me 430 6-OCF₃ CF₃ H 431 6-OCF₃ Cl H 4326-OCF₃ Cl Me

Example 424

2-Chloro-N-[3,5-dichloro-4-(4-chloro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(424). ¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.37 (d, J=8.3 Hz, 1H)8.21 (d, J=1.0 Hz, 1H), 8.00 (dd, J=8.3, 1.1 Hz, 1H), 7.96 (dd, J=8.1,0.9 Hz, 1H), 7.55 (dd, J=8.0, 0.9 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.33(s, 2H).MS (EI):m/z 585 (M−H).

Example 425

2,4-Dichloro-N-[3,5-dichloro-4-(4-chloro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(425). ¹H NMR (400 MHz, DMSO-d₆) δ 11.50 (s, 1H), 8.16 (d, J=8.6 Hz,1H), 7.98-7.94 (m, 2H), 7.70 (dd, J=8.6, 2.1 Hz, 1H), 7.55 (dd, J=7.9,0.8 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.30 (s, 2H). MS (EI): m/z 551(M−H).

Example 426

2,4-Dichloro-N-[3,5-dichloro-4-(4-chloro-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(426). ¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H), 8.19 (s, 1H), 7.96 (d,J=8.0 Hz, 1H), 7.90 (s, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.36 (t, J=8.0 Hz,1H), 7.31 (s, 2H), 2.40 (s, 3H). MS (EI): m/z 565 (M−H).

Example 427

2-Chloro-N-[3,5-dichloro-4-(4-methoxy-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(427). ¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.38 (d, J=8.3 Hz,1H), 8.20 (s, 1H), 8.00 (dd, J=8.3, 0.8 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H),7.32 (s, 2H), 7.30 (t, J=8.1 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 3.79 (s,3H). MS (EI): m/z 581 (M−H).

Example 428

2,4-Dichloro-N-[3,5-dichloro-4-(4-methoxy-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(428). ¹H NMR (400 MHz, DMSO-d₆) δ 11.49 (s, 1H), 8.17 (d, J=8.6 Hz,1H), 7.96 (d, J=2.1 Hz, 1H), 7.71 (dd, J=8.6, 2.1 Hz, 1H), 7.51 (d,J=8.1 Hz, 1H), 7.30 (t, J=8.1 Hz, 1H), 7.28 (s, 2H), 7.01 (d, J=8.2 Hz,1H), 3.81 (s, 3H). MS (EI): m/z 547 (M−H).

Example 429

2,4-Dichloro-N-[3,5-dichloro-4-(4-methoxy-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(429). ¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 8.20 (s, 1H), 7.90 (s,1H), 7.51 (d, J=8.1 Hz, 1H), 7.30 (t, J=8.1 Hz, 1H), 7.29 (s, 2H), 7.01(d, J=8.2 Hz, 1H), 3.81 (s, 3H), 2.41 (s, 3H). MS (EI): m/z 561 (M−H).

Example 430

2-Chloro-N-[3,5-dichloro-4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(430). ¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 8.38 (d, J=8.2 Hz,1H), 8.20 (d, J=1.2 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H), 8.00 (dd, J=8.3,1.2 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.0 Hz, 1H), 7.32(s, 2H). MS (EI): m/z 635 (M−H).

Example 431

2,4-Dichloro-N-[3,5-dichloro-4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(431). ¹H NMR (400 MHz, DMSO-d₆) δ 11.49 (s, 1H), 8.18 (d,j=8.6 Hz, 1H),8.15 (d, J=1.7 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H),7.71 (dd, J=8.6, 2.1 Hz, 1H), 7.42 (dd, J=8.7, 2.1 Hz, 1H), 7.29 (s,2H). MS (EI): m/z 601 (M−H).

Example 432

2,4-Dichloro-N-[3,5-dichloro-4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl]-5-methyl-benzenesulfonamide(432). ¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 8.20 (s, 1H), 8.14 (d,J=1.7 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.42 (d, J=8.8, 2.0Hz, 1H), 7.30 (s, 2H), 2.41 (s, 3H). MS (EI): m/z 615 (M−H).

Example 433

4-Bromo-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-2-trifluoromethoxy-benzenesulfonamide(433).4-Bromo-N-[3,5-dichloro-4-(6-chlorobenzothiazol-2-yloxy)-phenyl]-2-trifluoromethoxy-benzenesulfonamidewas synthesized (83%) from3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and4-bromo-2-trifluoromethoxybenzenesulfonyl chloride (Maybridge) in asimilar manner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆)δ 11.37 (s, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H),7.91-7.87 (m, 2H), 7.68 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.7, 2.2 Hz, 1H),7.31 (s, 2H). MS (EI): m/z 645 (M−H).

Example 434

N-[3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]4-trifluoromethoxy-benzenesulfonamide(434).N-[3,5-Dichloro-4-(6-chlorobenzothiazol-2-yloxy)-phenyl]-4-trifluoromethoxy-benzenesulfonamidewas synthesized (83%) from3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and4-trifluoromethoxybenzenesulfonyl chloride (Maybridge) in a similarmanner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.16(s, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.03-7.98 (m, 2H), 7.68 (d, J=8.7 Hz,1H), 7.65 (d, J=8.2 Hz, 2H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.31 (s, 2H).MS (EI): m/z 567 (M−H).

Example 435

N-[3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-2-nitro-4-trifluoromethyl-benzenesulfonamide(435).N-[3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-2-nitro-4-trifluoromethyl-benzenesulfonamidewas synthesized (48%) from3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and2-nitro-4-trifluoromethylbenzenesulfonyl chloride (Aldrich) in a similarmanner as described in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.65(br s, 1H), 8.61 (s, 1H), 8.32-8.28 (m, 2H), 8.15 (d, J=2.2 Hz, 1H),7.68 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.34 (s, 2H). MS(EI): m/z 596 (M−H).

Example 436

4-Acetyl-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide(436).4-Acetyl-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamidewas synthesized (36%) from3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and4-acetyl-benzenesulfonyl chloride (Fluka) in a similar manner asdescribed in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (br s,1H), 8.18 (dd, J=7.8, 1.7 Hz, 2H), 8.15 (d, J=2.2 Hz, 1H), 8.01 (d, J7.8, 1.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.2 Hz, 1H),7.32 (s, 2H), 2.63 (s, 3H). MS (EI): m/z 525 (M−H).

Example 437

Compound 437 was synthesized in a similar manner as described in Example334, from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine(420) and corresponding arylsulfonyl chloride.

Ar

Product 40 mg 30 mg 30 mg 40 mg MS 531(M − H) 515(M − H) 629(M − H)557(M − H) Ar

Product 10 mg 25 mg 10 mg 10 mg MS 551(M − H) 585(M − H) 601(M − H)567(M − H) Ar

Product 40 mg 15 mg 40 mg MS 601(M − H) 528(M − H) 547(M − H)

Example 438

2-Chloro-N-[3,5-dichloro-4-(6-nitro-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(438). To a solution of2-chloro-N-(3,5-dichloro-4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide(421, 1.52 g, 3.41 mmol) in 10 mL of DMF, was added NaH (Aldrich, 288mg, 60%, 7.2 mmol). The mixture was stirred for 10 min, then2-chloro-6-nitrobenzothiazole (411, 765 mg, 3.56 mmol) was added. Thereaction mixture was stirred until no 421 remained by TLC. The mixturewas diluted with EtOAc and 2N HCl, extracted 3× with EtOAc (100 mL). Theorganic layers were washed twice with a brine solution (100 mL), driedover Na₂SO₄ and concentrated. The residue was purified by chromatography(15%-20% EtOAc/hexanes) to give 1.5 g (74%) of product. ¹H NMR (400 MHz,DMSO-d₆) δ 11.69 (s, 1H), 9.08 (d, J=2.4 Hz, 1H), 8.38 (d, J=8.3 Hz,1H), 8.26 (dd, J=9.0, 2.4 Hz, 1H), 8.22 (s, 1H), 8.00 (d, J=8.4 Hz, 1H),7.87 (d, J=9.0 Hz, 1H), 7.33 (s, 2H). MS (EI): m/z 596 (M−H).

Examples 439-459

The compounds listed in Table 19 were prepared from compounds 421-423and 409-416 in a similar manner as described in Example 438.

TABLE 19

Compound X A B 438 6-NO₂ Cl Cl 441 6-SO₂Me Cl Cl 442 6-NO₂ Cl H 4456-SO₂Me Cl H 446 6-SO₂Me H H 447 6-NO₂ H H 450 6-Cl H H 451 6-OMe H H452 4-OMe H H 453 6-CF₃ H H 454 6-CN H H 455 5-NO₂ Cl Cl 458 5-SO₂Me ClCl 459 6-COMe Cl Cl

Example 439

N-[4-(6-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(439).N-[4-(6-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamidewas synthesized from2-chloro-N-[3,5-dichloro-4-(6-nitro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(438) in a similar manner as described in Examples 16-23 (Method A). ¹HNMR (400 MHz, DMSO-d₆) δ 8.36 (d, J=8.2 Hz, 1H), 8.20 (s, 1H), 7.99 (dd,J=8.3, 1.1 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.28 (s, 2H), 6.98 (d, J=2.2Hz, 1H), 6.64 (dd, J=8.6, 2.2 Hz, 1H). MS (EI): m/z 568 (M+H).

Example 440

2-Chloro-N-[3,5-dichloro-4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(440).2-Chloro-N-[3,5-dichloro-4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamidewas synthesized fromN-[4-(6-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(439) and methanesulfonyl chloride (Aldrich) in a similar manner asdescribed in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H),9.87 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.22 (s, 1H), 8.00 (d, J=8.2 Hz,1H), 7.83 (d, J=1.8 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.31 (s, 2H), 7.23(dd, J=8.8, 1.5 Hz, 1H). MS (EI): m/z 644 (M−H).

Example 441

2-Chloro-N-[3,5-dichloro-4-(6-methanesulfonyl-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(441). ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.67 (d, J=1.6 Hz,1H), 8.36 (d, J=8.3 Hz, 1H), 8.19 (s, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.94(dd, J=8.6, 1.8 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.29 (s, 2H), 3.24 (s,3H). MS (EI): m/z 629 (M−H).

Example 442

2-Chloro-N-[3-chloro-4-(6-nitro-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(442). ¹H NMR (400 MHz, DMSO 46) δ 11.43 (s, 1H), 9.04 (d, J=2.4 Hz,1H), 8.34 (d, J=8.2 Hz, 1H), 8.26 (dd, J=9.0, 2.5 Hz, 1H), 8.20 (d,J=1.0 Hz, 1H), 7.99 (dd, J=8.3, 1.1 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H),7.62 (d, J=8.9 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 7.21 (dd, J=8.9, 2.6 Hz,1H). MS (EI): m/z 562 (M−H).

Example 443

N-[4-(6-Amino-benzothiazol-2-yloxy)-3-chloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(443).N-[4-(6-Amino-benzothiazol-2-yloxy)-3-chloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamidewas synthesized from2-chloro-N-[3-chloro-4-(6-nitro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(442) in a similar manner as described in Examples 16-23 (Method A). ¹HNMR (400 MHz, DMSO-d₆) δ 8.31 (d, J=8.2 Hz, 1H), 8.18 (d, J=1.1 Hz, 1H),7.97 (dd, J=8.3, 1.2 Hz, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.30 (d, J=1.9 Hz,1H), 7.28 (d, J=8.7 Hz, 1H), 7.15 (dd, J=8.9, 2.6 Hz, 1H), 6.94 (d,J=2.2 Hz, 1H), 6.64 (dd, J=8.7, 2.3 Hz, 1H). MS (EI): m/z 534 (M+H).

Example 444

2-Chloro-N-[3-chloro-4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(444).2-Chloro-N-[3-dichloro-4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamidewas synthesized fromN-[4-(6-Amino-benzothiazol-2-yloxy)-3-chloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(443) and methanesulfonyl chloride (Aldrich) in a similar manner asdescribed in Examples 70-91.

¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 9.84 (s, 1H), 8.32 (d, J=8.3Hz, 1H), 8.19 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.79 (d, J=1.9 Hz, 1H),7.61 (d, J=8.7 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H),7.23 (dd, J=8.7, 1.5 Hz, 1H), 7.18 (dd, J=8.9, 1.9 Hz, 1H), MS (EI): m/z610 (M−H).

Example 445

2-Chloro-N-[3-chloro-4-(6-methanesulfonyl-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(445). ¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 8.63 (d, J=1.8 Hz,1H), 8.34 (d, J=8.2 Hz, 1H), 8.20 (d, J=1.1 Hz, 1H), 7.99 (dd, J=8.3,1.2 Hz, 1H), 7.93 (dd, J=8.6, 1.9 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.61(d, J=8.9 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 7.21 (dd, J=8.9, 2.6 Hz, 1H),3.24 (s, 3H). MS (EI): m/z 595 (M−H).

Example 446

2-Chloro-N-[4-(6-methanesulfonyl-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(446). ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 8.59 (d, J=1.3 Hz,1H), 8.28 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.93(dd, J=8.6, 1.9 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.41 (d, J=9.0 Hz, 2H),7.23 (d, J=8.9 Hz, 2H), 3.23 (s, 3H). MS (EI): m/z 561 (M−H).

Example 447

2-Chloro-N-[4-(6-nitro-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(447). ¹H NMR (400 MHz, DMSO-d₆ 11.15 (s, 1H), 9.00 (d, J=2.5 Hz, 1H),8.28 (d, J=9.2 Hz, 1H), 8.26 (dd, J=9.0, 2.5 Hz, 1H), 8.18 (s, 1H), 7.97(dd, J=8.3, 1.2 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.43 (d, J=9.0 Hz, 2H),7.24 (d, J=9.0 Hz, 2H). MS (EI): m/z 528 (M−H).

Example 448

N-[4-(6-Amino-benzothiazol-2-yloxy)-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(448).N-[4-(6-Amino-benzothiazol-2-yloxy)-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamidewas synthesized from2-chloro-N-[4-(6-nitro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(447) in a similar manner as described in Examples 16-23 (Method A). ¹HNMR (400 MHz, DMSO-d₆) δ 11.02 (br s, 1H), 8.25 (d, J=8.3 Hz, 1H), 8.16(d, J=1.0 Hz, 1H), 7.94 (dd, J=8.3, 1.0 Hz, 1H), 7.32-7.27 (m, 3H),7.20-7.15 (m, 2H), 6.93 (d, J=2.2 Hz, 1H), 6.65 (dd, J=8.6, 2.3 Hz, 1H),5.25 (br s, 2H). MS (EI): m/z 500 (M+H).

Example 449

2-Chloro-N-[4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(449).2-Chloro-N-[4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamidewas synthesized fromN-[4-(6-amino-benzothiazol-2-yloxy)-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(448) and methanesulfonyl chloride (Aldrich) in a similar manner asdescribed in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H),9.82 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.16 (d, J=1.1 Hz, 1H), 7.95 (dd,J=8.3, 1.2 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H),7.37-7.34 (m, 2H), 7.24 (dd, J=8.7, 2.2 Hz, 1H), 7.23-7.19 (m, 2H). MS(EI): m/z 576 (M−H).

Example 450

2-Chloro-N-[4-(6-chloro-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(450). ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.27 (d, J=8.2 Hz,1H), 8.17 (s, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.96 (dd, J=8.3, 1.2 Hz, 1H),7.65 (d, J=8.7 Hz, 1H), 7.44 (dd, J=8.6, 2.2 Hz, 1H), 7.40-7.35 (m, 2H),7.23-7.19 (m, 2H). MS (EI): m/z 517 (M−H).

Example 451

2-Chloro-N-[4-(6-methoxy-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(451). ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.26 (d, J=8.2 Hz,1H), 8.16 (d, J=1.2 Hz, 1H), 7.95 (dd, J=8.3, 1.2 Hz, 1H), 7.55 (d,J=8.9 Hz, 1H), 7.52 (d, J=2.6 Hz, 1H), 7.36-7.32 (m, 2H), 7.22-7.17 (m,2H), 7.00 (dd, J=8.9, 2.7 Hz, 1H), 3.77 (s, 3H). MS (EI): m/z 513 (M−H).

Example 452

2-Chloro-N-[4-(4-methoxy-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(452). ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.26 (d, J=8.2 Hz,1H), 8.16 (d, J=1.2 Hz, 1H), 7.95 (dd, J—8.3, 1.3 Hz, 1H), 7.45 (dd,J=8.0, 0.8 Hz, 1H), 7.36-7.31 (m, 2H), 7.27 (t, J=8.1 Hz, 1H), 7.23-7.18(m, 2H), 6.99 (dd, J=8.1, 0.6 Hz, 1H), 3.83 (s, 3H). MS (EI): m/z 513(M−H).

Example 453

2-Chloro-N-[4-(6-trifluoromethyl-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(453). ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 8.44 (s, 1H), 8.28 (d,J=8.3 Hz, 1H), 8.17 (d, J=0.9 Hz, 1H), 7.96 (dd, J=8.3, 1.2 Hz, 1H),7.84 (d, J=8.5 Hz, 1H), 7.73 (dd, J=8.6, 1.8 Hz, 1H), 7.43-7.37 (m, 2H),7.26-7.20 (m, 2H). MS (EI): m/z 551 (M−H).

Example 454

2-Chloro-N-[4-(6-cyano-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(454). ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 8.50 (d, J=1.5 Hz,1H), 8.28 (d, J=8.2 Hz, 1H), 8.17 (d, J=0.9 Hz, 1H), 7.96 (dd, J=8.3,1.0 Hz, 1H), 7.84 (dd, J=8.5, 1.6 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H),7.43-7.37 (m, 2H), 7.26-7.20 (m, 2H). MS (EI): m/z 508 (M−H).

Example 455

2-Chloro-N-[3,5-dichloro-4-(5-nitro-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(455). ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.48 (d, J=1.8 Hz,1H), 8.30 (d, J=8.9 Hz, 1H), 8.25-8.20 (m, 2H), 8.22 (s, 1H), 8.01 (d,J=8.2 Hz, 1H), 7.33 (s, 2H). MS (EI): m/z 596 (M−H).

Example 456

N-[4-(5-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(456).N-[4-(5-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamidewas synthesized from2-chloro-N-[3,5-dichloro-4-(5-nitro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(455) in a similar manner as described in Examples 16-23 (Method A). ¹HNMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=8.2 Hz, 1H), 8.19 (s, 1H), 8.00 (dd,J=8.3, 1.1 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.30 (s, 2H), 6.77 (d, J=2.1Hz, 1H), 6.63 (dd, J=8.6, 2.1 Hz, 1H). MS (EI): m/z 568 (M+H).

Example 457

2-Chloro-N-[3,5-dichloro-4-(5-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]4-trifluoromethyl-benzenesulfonamide(457).2-Chloro-N-[3,5-dichloro-4-(5-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamidewas synthesized fromN-[4-(5-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(456) and methanesulfonyl chloride (Aldrich) in a similar manner asdescribed in Examples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H),9.87 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.20 (s, 1H), 8.00 (d, J=8.3 Hz,1H), 7.91 (d, J=8.6 Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.32 (s, 2H), 7.21(dd, J=8.7, 1.6 Hz, 1H). MS (EI): m/z 644 (M−H).

Example 458

2-Chloro-N-[3,5-dichloro-4-(5-methanesulfonyl-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(458). ¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.38 (d, J=8.2 Hz,1H), 8.29 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 8.19 (d, J 1.6 Hz, 1H), 8.01(dd, J=8.2, 1.0 Hz, 1H), 7.88 (dd, J=8.5, 1.7 Hz, 1H), 7.34 (s, 2H),3.24 (s, 3H). MS (EI): m/z 629 (M−H).

Example 459

N-[4-(6-Acetyl-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide(459). ¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 8.68 (d, J=1.7 Hz,1H), 8.38 (d, J=8.2 Hz, 1H), 8.21 (s, 1H), 8.02-7.97 (m, 2H), 7.76 (d,J=8.5 Hz, 1H), 7.32 (s, 2H), 2.61 (s, 3H). MS (EI): m/z 629 (M−H).

Example 501

4-tert-Butyl-N-[3-chloro-5-(5-chloro-benzothiazole-2-yloxy)]-benzenesulfonamide(501).4-tert-Butyl-N-[3-chloro-5-(5-chloro-benzothiazole-2-yloxy]-benzenesulfonamidewas synthesized (62%) from aniline 273 using Method D described inExamples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 10.9 (s, 1H), 8.3 (d, J=8.6Hz, 1H), 7.82 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5Hz, 2H), 7.45 (dd, J=8.6, 2.1 Hz, 1H), 7.38 (dd, J=1.9, 1.9 Hz, 1H),7.16 (dd, J=1.9, 1.9 Hz, 1H), 7.12 (dd, J=1.8, 1.8 Hz, 1H), 1.3 (s, 9H).MS (EI): m/z 505 (100, M−H), 506 (33, M−H), 507 (94, M−H), 508 (30,M−H), 509 (15, M−H).

Example 502

N-[3-Chloro-5-(5-chloro-benzothiazole-2-yloxy)-phenyl]-2,5-dimethoxybenzenesulfonamide(502).N-[3-Chloro-5-(5-chloro-benzothiazole-2-yloxy)-phenyl]-2,5-dimethoxybenzenesulfonamidewas synthesized (55%) from aniline 273 using Method D described inExamples 70-91. ¹H NMR (400 MHz, DMSO-d₆) δ 10.8 (s, 1H), 8.1 (d, J=8.6Hz, 1H), 7.8 (d, J=2.1 Hz, 1H), 7.45 (dd, J=8.6, 2.1 Hz, 2H), 7.34-7.28(m, 2H), 7.23 (dd, J=9.0, 3.0 Hz, 1H), 7.18 (d, J=9.1 Hz, 1H), 7.15-7.1(m, 2H), 3.9 (s, 3H), 3.6 (s, 3H). MS (EI): m/z 509 (100, M−H), 510 (28,M−H), 511 (64, M−H), 512 (22, M−H), 513 (18, M−H).

Example 503

2-Chloro-N-[3-chloro-4-(4-chloro-benzothiazol-2-oxy)-phenyl]4-trifluoromethylbenzenesulfonamide(503).2-Chloro-N-[3-chloro-4-(4-chlorobenzothiazol-2-oxy)-phenyl]-4-trifluoromethylbenzenesulfonamidewas synthesized (84%) in a similar manner as described in Example 424.¹H NMR (400 MHz, DMSO-d₆) δ 11.4 (s, 1H), 8.33 (d, J=8.9 Hz, 1H), 8.2(s, 1H), 7.99 (d, J=8.3, Hz, 2H), 7.93 (d, J=8.0 Hz, 1H), 7.62 (d,J=9.0, Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.22 (dd,J=9.0, 2.5 Hz, 1H). MS (EI): m/z 551 (92, M−H), 552 (23, M−H), 553 (100,M−H), 554 (25, M−H), 555 (40, M−H).

Example 504

2-Chloro-N-[3-chloro-4-(4-methyl-benzothiazol-2-oxy)-phenyl]-4-trifluoromethylbenzenesulfonamide(504).2-Chloro-N-[3-chloro-4-(4-methylbenzothiazol-2-oxy)-phenyl]4-trifluoromethylbenzenesulfonamidewas synthesized (45%) from phenol 422 in a similar manner as describedin Example 438. ¹H NMR (400 MHz, DMSO-d₆) δ 11.4 (s, 1H), 8.33 (d, J=8.2Hz, 1H), 8.2 (s, 1H), 7.99 (d, J=8.3, Hz, 1H), 7.73 (dd, J=7.2, 1.9 Hz,1H), 7.6 (d, J=8.9 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 7.3-7.28 (m, 1H),7.25 (d, J=7.4, Hz, 1H), 7.2 (d, J=8.4, 2.6 Hz, 1H), 2.35 (s, 3H). MS(EI): m/z 531 (100, M−H), 532 (28, M−H), 533 (75, M−H), 534 (16, M−H),535 (15, M−H).

Example 505

2-Chloro-N-[3,5-dichloro-4-(4-methyl-benzothiazol-2-oxy)-phenyl]4-trifluoromethylbenzenesulfonamide(505).2-Chloro-N-[3,5-dichloro-4-(4-methylbenzothiazol-2-oxy)-phenyl]-4-trifluoromethylbenzenesulfonamidewas synthesized (16%) from phenol 421 in a similar manner as describedin Example 438. ¹H NMR (400 MHz, DMSO-d₆) δ 11.6 (s, 1H), 8.38 (d, J=8.3Hz, 1H), 8.22 (s, 1H), 8.0 (d, J=8.3, Hz, 1H), 7.76 (dd, J=9.0, 2.9 Hz,1H), 7.34 (s, 2H), 7.28-7.22 (m, 2H), 2.35 (s, 3H). MS (EI): m/z 565(100, M−H), 567 (75, M−H), 568 (16, M−H), 569 (15, M−H).

Example 600

Using methods similar to Lehmann, et al., ibid., selected compoundsexhibited the following IC₅₀ values in a PPARγ ligand binding assayutilizing [³H]-BRL 49653 as the radioligand. IC₅₀ values are defined asthe concentration of test compounds required to reduce by 50% thespecific binding of [³H]-BRL 49653 and are represented by (+)<30 μM;(++)<10 μM; (+++)<1 μM.

TABLE 20 Compound PPARγ Binding IC₅₀ 3 +++ 4.1 +++ 4.2 +++ 4.3 +++ 5.2+++ 5.3 ++ 40 +++ 41 ++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 +++49 +++ 50 +++ 71 +++ 72 +++ 73 +++ 74 +++ 75 +++ 76 ++ 77 ++ 78 +++ 79+++ 80 +++ 81 +++ 82 +++ 83 +++ 84 +++ 85 +++ 86 +++ 87 +++ 88 +++ 89+++ 90 +++ 91 +++ 103 +++ 104 ++ 106 +++ 224 +++ 225 +++ 226 +++ 231 +++232 +++ 237 +++ 238 +++ 283 ++ 284 +++ 285 +++ 286 ++ 287 +++ 288 +++289 +++ 290 + 291 + 292 ++ 293 +++ 294 + 295 ++ 296 ++ 297 ++ 298 +++299 +++ 300 +++ 301 +++ 302 +++ 303 +++ 304 +++ 305 +++ 306 +++ 307 ++308 +++ 309 +++ 310 +++ 311 +++ 322 ++ 323 ++ 324 +++ 331 +++ 332 +++333 +++ 424 ++ 424 ++ 425 ++ 425 ++ 426 +++ 426 +++ 427 +++ 427 +++ 428+++ 428 +++ 429 +++ 429 +++ 433 +++ 434 ++ 435 +++ 436 ++ 438 +++ 440+++ 441 +++ 442 +++ 444 +++ 445 +++ 455 ++ 457 +++ 458 +++ 501 − 502 −503 + 504 + 505 +

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

1. A compound having the formula:

wherein A is Cl or CF₃; C is Cl or CF₃; D is H or CH₃; V is F or Cl; Xis a member selected from the group consisting of H, CH₃, COOH, andCO₂CH₃; and Y is a member selected from the group consisting of H, CO₂Hand CO₂CH₃; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, wherein V is Cl.
 3. The compound of claim 1,wherein X and Y are each H.
 4. The compound of claim 1, wherein A is Cl.5. The compound of claim 1, wherein A is CF₃.
 6. The compound of claim1, wherein D is H.
 7. The compound of claim 1, wherein A is Cl and D isH.
 8. The compound of claim 1, wherein A is Cl; C is Cl; and V is Cl. 9.The compound of claim 1, wherein C is CF₃.
 10. The compound of claim 1,wherein A is Cl; C is Cl; V is Cl, D is CH₃, and X and Y are each H. 11.The compound of claim 1, wherein A is Cl; C is Cl; V is Cl, D is H, andX and Y are each H.
 12. A composition comprising a pharmaceuticallyacceptable carrier or excipient and a compound having the formula:

wherein A is Cl or CF₃; C is Cl or CF₃; D is H or CR₃; V is F or Cl; Xis a member selected from the group consisting of H, CH₃, COOH, andCO₂CH₃; and Y is a member selected from the group consisting of H, CO₂Hand CO₂CH₃; or a pharmaceutically acceptable salt thereof.
 13. Thecomposition of claim 12, wherein V is Cl.
 14. The composition of claim12, wherein X and Y are each H.
 15. The composition of claim 12, whereinA is Cl.
 16. The composition of claim 12, wherein A is CF₃.
 17. Thecomposition of claim 12, wherein D is H.
 18. The composition of claim12, wherein A is Cl and D is H.
 19. The composition of claim 12, whereinA is Cl; C is Cl; and V is Cl.
 20. The composition of claim 12, whereinC is CF₃.
 21. The composition of claim 12, wherein A is Cl; C is Cl; Vis Cl, D is CH₃, and X and Y are each H.
 22. The composition of claim12, wherein A is Cl; C is Cl; V is Cl, D is H, and X and Y are each H.